Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: COL2A1
SNOMEDCT: 1010668008, 111255008, 205483007, 240241003, 254061001, 254064009, 278713008, 53974002, 702339001, 702350003, 720826006, 773727009, 78675000; ICD10CM: M91.1, M91.2, Q77.0, Q77.7;
Cytogenetic location: 12q13.11 Genomic coordinates (GRCh38): 12:47,972,967-48,006,212 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q13.11 | ?Epiphyseal dysplasia, multiple, with myopia and deafness | 132450 | Autosomal dominant | 3 |
| ?Vitreoretinopathy with phalangeal epiphyseal dysplasia | 619248 | Autosomal dominant | 3 | |
| Achondrogenesis, type II or hypochondrogenesis | 200610 | Autosomal dominant | 3 | |
| Avascular necrosis of the femoral head | 608805 | Autosomal dominant | 3 | |
| Czech dysplasia | 609162 | Autosomal dominant | 3 | |
| Kniest dysplasia | 156550 | Autosomal dominant | 3 | |
| Legg-Calve-Perthes disease | 150600 | Autosomal dominant | 3 | |
| Osteoarthritis with mild chondrodysplasia | 604864 | Autosomal dominant | 3 | |
| Platyspondylic skeletal dysplasia, Torrance type | 151210 | Autosomal dominant | 3 | |
| SED congenita | 183900 | Autosomal dominant | 3 | |
| SMED Strudwick type | 184250 | Autosomal dominant | 3 | |
| Spondyloepiphyseal dysplasia, Stanescu type | 616583 | Autosomal dominant | 3 | |
| Spondyloperipheral dysplasia | 271700 | Autosomal dominant | 3 | |
| Stickler syndrome, type I | 108300 | Autosomal dominant | 3 | |
| Stickler syndrome, type I, nonsyndromic ocular | 609508 | Autosomal dominant | 3 |
Collagens are major structural components of the extracellular matrix. Type II collagen, also called cartilage collagen, is the major collagen synthesized by chondrocytes. The same type of collagen occurs in the vitreous. Type II collagen is composed of 3 alpha-1(II) chains. These are synthesized as larger procollagen chains, which contain N- and C-terminal amino acid sequences called propeptides. After secretion into the extracellular matrix, the propeptides are cleaved, forming the mature type II collagen molecule (summary by Strom and Upholt, 1984 and Cheah et al., 1985).
Strom and Upholt (1984) isolated overlapping genomic DNA clones containing most of the coding sequences for chicken type II procollagen. They found that the chicken type II gene is 2 to 3 times more compact than the chicken type I alpha-2 gene (COL1A2; 120160) due to smaller introns. The coding sequence shows about 75% homology with type I alpha-1 (COL1A1; 120150) and 63 to 67% homology with type I alpha-2 and type III (COL3A1; 120180) sequences. Base composition and codon usage of type II are very similar to alpha-1(I) and different from alpha-2(I) and type III. The chicken type II gene appears to be present in single copy per haploid genome. Using probes corresponding to the chicken COL2A1 procollagen gene to screen a recombinant human DNA library, Strom and Upholt (1984) isolated a portion of the human COL2A1 gene.
Sangiorgi et al. (1984) isolated from a cartilage cDNA library a bovine clone encoding the pro-alpha-1(II) collagen chain. Because of the close homology of bovine and human collagens, the bovine clone could be used to isolate the corresponding gene from a human genomic library.
By comparison of amino acid sequences, van der Rest et al. (1986) showed that chondrocalcin is the C-propeptide of type II procollagen. Chondrocalcin is a calcium-binding protein found in developing fetal cartilage matrix and in growth plate cartilage when and where mineralization occurs in the lower hypertrophic zone. It appears to play a role in enchondral ossification. The new evidence on its identity to C-propeptide indicates that it is also important in assembly of the triple helix of type II collagen. See 156550 for evidence of abnormal processing of the C-propeptide of type II collagen resulting in imperfect fibril assembly and the clinical disorder called Kniest dysplasia.
Studying the gerbil, Slepecky et al. (1992) demonstrated that types II and IX (120210) collagen show colocalization in the inner ear.
Wu and Eyre (1995) provided evidence that what was formerly termed the alpha-3 chain of type XI collagen (COL11A3) is actually transcribed from the COL2A1 gene.
By analysis of DNA from human-mouse cell hybrids, Sangiorgi et al. (1984) localized the COL2A1 gene to chromosome 12. The results were confirmed by similar experiments with the bovine cDNA probe. Using a cloned gene as a probe on Southern blots of DNA from a panel of interspecies somatic cell hybrids, Solomon et al. (1985) also assigned the COL2A1 locus to chromosome 12.
By somatic cell hybrid studies and in situ hybridization, Huerre-Jeanpierre et al. (1986) assigned COL2A1 to 12q13.1-q13.2 and COL3A1 to 2q31-q32.3. Law et al. (1986) used a cosmid clone of the entire COL2A1 gene in Southern analysis of DNA from somatic cell hybrids containing segments of chromosome 12. Two hybrids contained a similar terminal deletion of 12q14.3-qter but 1 was positive for the gene and 1 negative. This led Law et al. (1986) to conclude that the gene is located in 12q14.3.
Takahashi et al. (1990) described a 'new' nonisotopic method of in situ hybridization. It involved replication of R-bands by incorporation of bromodeoxyuridine (BrdU) into cells synchronized with thymidine. Fluorescent signals could be detected on R-banded prometaphases stained with propidium iodide. They illustrated the strength of the system by refining the localization of the COL2A1 gene to 12q13.11-q13.12. By nonisotopic in situ hybridization, Takahashi et al. (1990) showed that the COL2A1 gene is immediately proximal to the fragile site fra(12)(q13.1).
Lovell-Badge et al. (1987) introduced a cosmid containing the human type II collagen gene, including 4.5 kb of 5-prime and 2.2 kb of 3-prime flanking DNA, into mouse embryonic cells in vitro. Human type II collagen mRNA was found only in tissues that showed transcription from the endogenous (mouse) gene, and human type II collagen was found in cartilage. The findings indicated that the cis-acting requirements for correct temporal and spatial regulation of the gene were fulfilled by the introduced DNA.
Several skeletal and ocular disorders have been found to be caused by mutation in the COL2A1 gene. These are sometimes referred to as type II collagenopathies.
Barat-Houari et al. (2016) provided a review of COL2A1 variants in type II collagenopathies, including 415 different mutations in 598 probands.
Spondyloepiphyseal Dysplasia Congenita
The first evidence for a defect in COL2A1 in SED congenita (183900) and in Langer-Saldino achondrogenesis (200610) was the finding of abnormal patterns of digestion of type II collagen by cyanogen bromide, as demonstrated by Horton (1987). Confirmation of the defect in SED congenita was provided by demonstration of mutation in COL2A1 (120140.0001 and 120140.0002).
Achondrogenesis Type II
Godfrey and Hollister (1988) presented evidence that the patient they studied with a lethal perinatal form of short-limbed dwarfism (200610) was heterozygous for an abnormal pro-alpha-1(II) chain which impaired the assembly and/or folding of type II collagen. Vissing et al. (1989) demonstrated that the mutation in the type II procollagen gene was a single base change that converted the codon for glycine (GGC) at amino acid 943 to a codon for serine (AGC) (120140.0002).
Stickler Syndrome, Type I
Francomano et al. (1987, 1987) demonstrated absolute linkage of COL2A1 and Stickler syndrome (STL1; 108300); a total lod score of 3.96 at theta = 0.0 was obtained. In a family with Stickler syndrome, Ahmad et al. (1990, 1991) identified a mutation in the COL2A1 gene (120140.0005).
Mutation in the COL2A1 gene (120140.0014) has also been found in a nonsyndromic ocular form of type I Stickler syndrome (609508).
In a patient with Stickler syndrome type I, who had a clinical diagnosis of otospondylomegaepiphyseal dysplasia (OSMED; 215150), Miyamoto et al. (2005) identified a splice acceptor mutation in intron 10 (709-2A-G; 120140.0048) of the COL2A1 gene.
Osteoarthritis Associated with Chondrodysplasia
Knowlton et al. (1989) found tight linkage (no recombination) of the COL2A1 gene with a precocious form of familial primary generalized osteoarthritis (OA) associated with chondrodysplasia (604864). In the full report of this family, Knowlton et al. (1990) stated that a 16-year-old male had osteoarthritis of the middle metacarpophalangeal joints and hips as well as bilateral osteochondritis dissecans of the capitellum. A 38-year-old female also had osteoarthritis of the spine, wrists, proximal interphalangeal joints, and distal interphalangeal joints. Vertebral bodies were flattened with Schmorl nodes. Linkage analysis suggested that the mutation is in the COL2A1 locus with a maximum lod score of 2.39 in multipoint analysis. Morphometrics demonstrated a short trunk producing abnormally low upper segment to lower segment ratio. A mutation in the COL2A1 gene (120140.0003) in affected members of the kindred described by Knowlton et al. (1990) was identified by Ala-Kokko et al. (1990).
Nelson et al. (1998) presented further evidence that the synthesis of type II collagen is increased in osteoarthritis. Using an immunoassay, they showed that the content of the C-propeptide of type II procollagen, released extracellularly from the newly synthesized molecule, is directly related to the synthesis of this molecule in healthy and osteoarthritic articular cartilage. In OA cartilage, the content of the type II procollagen is often markedly elevated (mean 7.6-fold). The increase in type II procollagen in OA cartilage was not reflected in serum, where a significant reduction was observed.
Kniest Dysplasia
Wilkin et al. (1999) noted that 10 of 12 previously described dominant mutations in the COL2A1 gene in patients with Kniest dysplasia caused small deletions in the type II collagen molecule. They added 4 new mutations, bringing the total to 16. All 4 new mutations were also small deletions; a fifth patient was found to have a previously reported 28-bp deletion (120140.0012).
COL2A1 has 10 in-frame CGA codons that can mutate to TGA stop codons by a methylation-deamination mechanism. Wilkin et al. (2000) analyzed these 10 codons using restriction endonuclease analysis or allele-specific amplification. Mutations at 5 COL2A1 CGA codons were identified in 8 of 40 patients with Stickler syndrome, suggesting that these are common sites of mutation in this disorder.
Korkko et al. (2000) performed COL2A1 mutation analysis on 12 patients with achondrogenesis type II/hypochondrogenesis, using conformation sensitive gel electrophoresis, followed by sequencing. Mutations were identified in all patients. Ten had single base substitutions, 1 had a change in a consensus RNA splice site, and 1 was an 18-bp deletion of coding sequences. Mutations were widely distributed across the gene.
In 2 sporadic cases of the Torrance type of platyspondylic skeletal dysplasia (151210), Nishimura et al. (2004) identified de novo mutations in the COL2A1 gene (120140.0039-120140.0040).
Avascular Necrosis of the Femoral Head and Legg-Calve-Perthes Disease
Avascular necrosis of the femoral head (see ANFH1, 608805) causes disability that often requires surgical intervention. Most cases of ANFH are sporadic, but Liu et al. (2005) identified 3 families in which there was autosomal dominant inheritance of the disease with mapping of the phenotype to 12q13. Liu et al. (2005) carried out haplotype analysis in the families, selected candidate genes from the critical interval for an ANFH on 12q13, and sequenced the promoter and exonic regions of the COL2A1 gene from persons with inherited and sporadic forms of ANFH. In 2 of the families they identified the same gly1170-to-ser mutation (120140.0043), on different haplotype backgrounds. The gly717-to-ser mutation was detected in the third family (120140.0044).
Miyamoto et al. (2007) identified the gly1170-to-ser mutation (120140.0043) in affected members of a Japanese family with an autosomal dominant disorder manifesting as Legg-Calve-Perthes disease (LCPD; 150600), a form of ANFH in growing children.
In a 40-year-old man who was diagnosed with avascular necrosis of the femoral head at 18 years of age and underwent bilateral hip replacement at 33 years of age, Kannu et al. (2011) identified a heterozygous missense mutation in the C-propeptide region of the COL2A1 gene (120140.0054). The authors noted that mutations in the C-propeptide region typically cause significant skeletal findings unlike those found in this patient.
Other Disorders Caused by COL2A1 Mutations
Other disorders caused by mutation in the COL2A1 gene include spondylometaphyseal dysplasia (SMD; 184252; see 120140.0013); Strudwick type of spondyloepimetaphyseal dysplasia (184250; see 120140.0017); multiple epiphyseal dysplasia with myopia and conductive deafness (132450; see 120140.0029); spondyloperipheral dysplasia (271700; see 120140.0030); platyspondylic skeletal dysplasia, Torrance type (151210; see 120140.0039); Czech dysplasia (609162; see 120140.0018); rhegmatogenous retinal detachment (see 609508; see 120140.0045); vitreoretinopathy with phalangeal epiphyseal dysplasia (120140.0037); and Stanescu type of spondyloepiphyseal dysplasia (SEDSTN; 616583; see 120140.0055).
Machol et al. (2017) reported 2 unrelated patients diagnosed with the corner fracture type of spondylometaphyseal dysplasia (see SMDCF, 184255) in whom heterozygous mutations in the COL2A1 gene were reported, G345D and G945S, respectively. The G345D mutation had previously been detected in a patient diagnosed with the Strudwick type of spondyloepimetaphyseal dysplasia (SEMDSTWK, 184250) by Barat-Houari et al. (2016), and the G945S mutation had previously been reported by Terhal et al. (2015) in 5 affected members of a Dutch family diagnosed with mild spondyloepiphyseal dysplasia congenita resembling multiple epiphyseal dysplasia (see EDM1, 132400). Noting that Walter et al. (2007) also described a COL2A1-mutated patient with primarily metaphyseal involvement and apparent 'corner fractures,' Machol et al. (2017) suggested that SMDCF may be a heterogeneous disorder with a subset of patients showing overlap with type II collagenopathies.
Somatic Mutation in Chondrosarcoma
Tarpey et al. (2013) reported comprehensive genomic analyses of 49 individuals with chondrosarcoma (215300) and identified hypermutability of the major cartilage collagen gene COL2A1, with insertions, deletions, and rearrangements identified in 37% of cases. The patterns of mutation were consistent with selection for variants likely to impair normal collagen biosynthesis. In addition, Tarpey et al. (2013) identified mutations in IDH1 (147700) or IDH2 (147650) (59%), TP53 (191170) (20%), the RB1 pathway (see 614041) (33%), and Sonic hedgehog signaling (600725) (18%).
Associations Pending Confirmation
Helfgott et al. (1991) suggested that collagen type II may not only be involved in the sensorineural deafness that accompanies hereditary disorders such as spondyloepiphyseal dysplasia congenita and Stickler syndrome but may also be the target of an autoimmune process in some cases of acquired bilateral progressive sensorineural hearing loss.
Liberfarb et al. (2003) performed genotype/phenotype correlations in 47 affected members from 10 families with 7 defined mutations in the COL2A1 gene based on review of medical records and clinical evaluation of 25 additional family members from 6 of the 10 families. The ages ranged from 2 to 73 years with a mean age of 34.7 years. The classic Stickler phenotype was expressed clinically in all 10 Stickler families with COL2A1 mutations and all had evidence of vitreous degeneration type 1. Myopia was present in 41 of 47 family members. There was considerable interfamilial and intrafamilial variability in clinical expression. The prevalence of certain clinical features was a function of age. Liberfarb et al. (2003) concluded that it is difficult to predict the severity of the phenotype based on the genotype of COL2A1 mutation.
Nishimura et al. (2005) searched for COL2A1 mutations in 56 families suspected of having type II collagenopathies and found 38 mutations in 41 families. There were no radiologic differences between the cases with and those without mutations. Phenotypes for all 22 missense mutations and 1 in-frame deletion in the triple-helical region fell along the SED spectrum. Glycine-to-serine substitutions resulted in alternating zones that produced more severe and milder phenotypes; glycine-to-nonserine residue substitutions exclusively created more severe phenotypes. The gradient of the SED spectrum did not necessarily correlate with the occurrence of extraskeletal manifestations. All 9 truncation or splice site mutations in the triple-helical or N-propeptide region caused either Stickler syndrome type I or Kniest dysplasia (156550), and extraskeletal changes were consistently present in both phenotypes. All 6 C-propeptide mutations produced a range of atypical skeletal phenotypes and created ocular, but not otolaryngologic, changes.
Hoornaert et al. (2006) noted that the majority of COL2A1 mutations are substitutions of obligatory glycine residues in the triple-helical domain; of the few nonglycine missense mutations that have been reported, arginine-to-cysteine substitutions predominate. Hoornaert et al. (2006) investigated the clinical and radiologic phenotype in 11 patients in whom they had identified arg-to-cys mutations in the COL2A1 gene. Each mutation resulted in a rather constant and site-specific phenotype, but a perinatally lethal disorder was never observed. Spondyloarthropathy with normal stature and no ocular involvement were features of patients with the R75C (120140.0018), R519C (120140.0003), or R1076C mutation. Short third and fourth toes were a distinguishing feature of the R75C mutation, and brachydactyly with enlarged finger joints was a key feature of the R1076C substitution. Stickler dysplasia with brachydactyly was observed in patients with the R704C (120140.0029) mutation. The R365C (120140.0033) and R789C (120140.0016) mutations resulted in classic Stickler dysplasia and spondyloepiphyseal dysplasia congenita, respectively.
Barat-Houari et al. (2016) screened the COL2A1 gene in a cohort of 136 probands with clinical and/or radiographic suspicion of a type II collagen disorder. The authors identified 66 different mutations, spread throughout the COL2A1 gene, in 71 probands. They noted that the molecular spectrum was different across various diseases, e.g., all variant types were seen in Stickler syndrome, whereas only missense variants were seen in SEDC. Barat-Houari et al. (2016) stated that their results demonstrated the limits of focusing on a single gene for genetic diagnosis, given the lack of clear phenotype-to-genotype correlation, and suggested that a targeted next-generation sequencing approach should be used to screen patients with skeletal dysplasias for other candidate genes.
Reviews
Kuivaniemi et al. (1997) tabulated all reported disease-producing mutations in the COL2A1 gene.
Vandenberg et al. (1991) found that transgenic mice carrying a partially deleted human COL2A1 gene developed the phenotype of a chondrodysplasia with dwarfism, short and thick limbs, short snout, cranial bulge, cleft palate, and delayed mineralization of bone. In cultured chondrocytes from transgenic mice, the minigene was expressed as shortened pro-alpha-1(II) chains that were disulfide-linked to normal mouse type II collagen chains. Therefore, the phenotype was probably explained by depletion of endogenous mouse type II procollagen through the phenomenon of procollagen suicide. Garofalo et al. (1991) generated transgenic mice harboring a glycine-to-cysteine mutation at residue 85 of the triple-helical domain of mouse type II collagen. Offspring displayed severe chondrodysplasia with short limbs and trunk, craniofacial deformities, and cleft palate. Affected pups died of acute respiratory distress caused by inability to inflate the lungs at birth. Electron microscopic analysis showed a pronounced decrease in the number of typical thin cartilage collagen fibrils, distention of the rough endoplasmic reticulum of chondrocytes, and the presence of abnormally large banded collagen fibril bundles. Garofalo et al. (1991) postulated that the abnormally thick collagen bundles were related to a defect in crosslinking. They pointed out similarities to the chondrodysplasias of the spondyloepiphyseal dysplasia group.
Li et al. (1995) used homologous recombination in embryonic stem cells to prepare transgenic mice with an inactivated COL2A1 gene. Heterozygous mice had minimal phenotypic changes. Homozygous mice were delivered vaginally but died either just before or shortly after birth. In these mice the cartilage consisted of highly disorganized chondrocytes with a complete lack of extracellular fibrils discernible by electron microscopy. There was no endochondral bone or epiphyseal growth plate in long bones; however, many skeletal structures such as the cranium and ribs were normally developed and mineralized. Li et al. (1995) concluded that a well-organized cartilage matrix is required as a primary tissue for development of some components of the skeleton but is not essential for others.
Gaiser et al. (2002) constructed a transgenic mouse model of SED congenita using a type II collagen transgene with an arg789-to-cys change (R789C; 120140.0016) in combination with a murine Col2a1 promoter directing the gene expression to cartilage. Mice carrying the transgene were shorter overall, had shorter limbs with disorganized growth plates, a short nose, cleft palate, and died at birth. Using cell culture experiments and molecular modeling, Gaiser et al. (2002) suggested that this Y-position mutation acts in a dominant-negative way, resulting in destabilization of collagen molecules during assembly, reduction in the number of fibrils formed, and abnormal cartilage template function. Donahue et al. (2003) identified a naturally occurring arg1147-to-cys mutation in the Col2a1 gene in the mouse which resulted in recessive SED congenita with a less severe phenotype, as indicated by the fact that the mice survived to adulthood and reproduced normally.
The following is an account of a temporarily confusing aspect of the collagen II gene. Weiss et al. (1982) described a collagen gene isolated in a 40-kb cosmid clone, cosHco11, which has some sequence homology to the alpha-1(I) gene, but which is clearly a different gene. Using this collagen alpha-1(I)-like probe on Southern blots of DNA from somatic cell hybrids, Solomon et al. (1984) found that the gene segregated with chromosome 12 and is not syntenic with the alpha-2(I) gene assigned to chromosome 7 (120160) or the alpha-1(I) gene assigned to chromosome 17 (120150). This gene contains an RFLP with HindIII. A 300-basepair deletion in the alpha-1(I)-like gene mapped by Solomon et al. (1984) was demonstrated by Pope et al. (1984) in a father and son with one form of Ehlers-Danlos syndrome II (EDS II; 130010). The deletion was found at or near the 3-prime end of the gene and was not identified in other cases of EDS II or in 400 normal controls. It was found, however, in 4 babies with lethal osteogenesis imperfecta congenita. The father and son with EDS II and the deletion showed altered collagen fibril size and shape. Subsequently, the 'alpha-1(I)-like' gene was shown to encode the alpha subunit of cartilage collagen and it was further shown that there is a polymorphism in this gene that is frequent in Asiatic Indians (Sykes et al., 1985). Of the 4 cases of Pope et al. (1984), 3 originated from India or Sri Lanka. This experience illustrates the hazards of confusing polymorphism with pathology.
Meulenbelt et al. (1996) determined the allele frequencies and pairwise linkage disequilibria of RFLPs distributed over the COL2A1 gene in a population of unrelated Dutch Caucasians. Their data indicated that disease-related population studies should include a minimum of 4 RFLPs.
Strom (1984) purported to find abnormality of the type II collagen gene in achondroplasia. If such a defect were present, one would expect ocular abnormality in achondroplasia inasmuch as type II collagen is present in vitreous. SED congenita is a more plausible candidate for a structural defect of type II collagen because it is a dominant disorder that combines skeletal dysplasia with vitreous degeneration and deafness (experimental studies with antibodies to type II collagen indicate that this collagen type is represented in the inner ear; Yoo et al., 1983). The work of Strom (1984) may be technically flawed.
In a patient with autosomal dominant spondyloepiphyseal dysplasia congenita (183900), Lee et al. (1989) demonstrated a heterozygous in-frame deletion of exon 48 of the COL2A1 gene, which encodes amino acid residues 964-999 of the triple-helical of domain of the protein.
In a patient described by Godfrey and Hollister (1988) with 'a relatively mild case of type II achondrogenesis-hypochondrogenesis' (see 200610), Vissing et al. (1989) demonstrated heterozygosity for a G-to-A transition in exon 46 of the COL2A1 gene that converted glycine-943 to serine (G943S). The substitution disrupted the invariant Gly-X-Y structural motif necessary for perfect helix formation and led to an excessive overmodification, intracellular retention, and reduced secretion of type II collagen.
In the kindred described by Knowlton et al. (1990) with osteoarthritis associated with mild chondrodysplasia (OSCDP; 604864), Ala-Kokko et al. (1990) found a heterozygous change from arginine to cysteine at position 519 of the alpha-1(II) chain. In an affected family member who underwent hip surgery, Eyre et al. (1991) demonstrated that approximately one-fourth of the alpha-1(II) chains present in the polymeric extracellular collagen of the patient's cartilage contained the arg519-to-cys substitution. The protein exhibited other abnormal properties including disulfide-bonded alpha-1(II) dimers and signs of posttranslational overmodification.
Holderbaum et al. (1993) referred to 2 additional families with precocious-onset osteoarthritis and mild chondrodysplasia caused by the arg519-to-cys mutation. They reported studies suggesting that the mutation arose independently in at least 2 of the 3 known affected families.
Williams et al. (1995) found the arg519-to-cys mutation in a fourth family with early-onset osteoarthritis and late-onset spondyloepiphyseal dysplasia.
Bleasel et al. (1998) reported that the arg519-to-cys mutation in COL2A1 had been identified in 5 families with mild spondyloepiphyseal dysplasia and precocious osteoarthritis. Haplotype analysis identified 3 distinct mutation-bearing haplotypes, with 3 families sharing a common haplotype. For the 3 distinct haplotypes to have derived from a single founder, 3 independent recombination events were required. Thus, the arg519 codon appears to represent a possible site of recurrent mutations in COL2A1, an uncommon phenomenon in collagen genes.
In a sporadic case of spondyloepiphyseal dysplasia (183900), Tiller et al. (1990) found an internal tandem duplication of 45 basepairs within exon 48 of COL2A1, resulting in the addition of 15 amino acids to the triple-helical domain of the protein. The abnormal molecule showed excessive posttranslational modification. The mutation was not carried by either parent, indicating a new dominant mutation. DNA sequence homology in the area of the duplication suggested that the mutation may have arisen by unequal crossover between related sequences.
In a family with Stickler syndrome (STL1; 108300), Ahmad et al. (1990, 1991) found a single base mutation altering the arginine at amino acid 732 of the triple-helical domain of COL2A1 to a stop codon. The mutation altered a CG dinucleotide and converted the codon CGA to TGA. This mutation was located in exon 40. Ahmad et al. (1991) noted that the mutation produced marked changes in the eye, which contains only small amounts of type II collagen, but had relatively mild effects on the many cartilaginous structures of the body that are rich in the same protein.
In a case of hypochondrogenesis (see 200610), Horton et al. (1992) detected a subtle mutation in the COL2A1 gene by use of a chondrocyte culture system and PCR-cDNA scanning analysis. Chondrocytes obtained from cartilage biopsies were dedifferentiated and expanded in monolayer culture and then redifferentiated by culture over agarose. Single-strand conformation polymorphism and direct sequencing analysis identified a G-to-A transition, resulting in substitution of glycine by serine at amino acid 574 in the triple-helical domain of type II procollagen. The morphologic assessment of cartilage-like structures produced in culture and electrophoretic analysis of collagens synthesized by the cultured chondrocytes suggested that the glycine substitution interfered with conversion of type II procollagen to collagen, impaired intracellular transport and secretion of the molecule, and disrupted collagen fibril assembly.
In a family with Stickler syndrome (STL1; 108300), Brown et al. (1992) found that 4 affected members had deletion of a single basepair resulting in a translational frameshift in exon 40 of the COL2A1 gene. The mutation was not found in any of 5 clinically unaffected family members or in any of 15 unrelated control patients. All affected members had abnormal vitreous syneresis and all had retinal perivascular pigmentation. Retinal detachments occurred in 3 of the 4 affected patients. Three of the 4 had peripheral cortical 'wedge' cataracts, and the fourth had extensive nuclear sclerosis. In all 4 affected patients, there were abnormalities of the palate: bilateral torus palatini, linea alba with submucous cleft palate, bifid uvula, and 'notched' hard palate. All patients reported severe joint pains, and radiologic changes suggesting epiphyseal dysplasia were found in all 4. One patient had had left total hip replacement at a relatively young age. Palatal and ocular changes were illustrated by photographs, and radiographs of the skeletal changes were presented. The deletion was reported to involve a thymidine nucleotide at position 18 of exon 40. This resulted in a translational frameshift, with formation of a nonsense codon, TGA, downstream in exon 42, leading to premature termination of translation at that point. The deletion also created a new MspI restriction site.
In an infant with a severe form of skeletal dysplasia who required continuous respiratory support until his death at 3 months of age, Bogaert et al. (1992) demonstrated a gly853-to-glu mutation resulting from a GGA-to-GAA transition in the COL2A1 gene. The patient was heterozygous. The radiologic features were thought to be those of hypochondrogenesis (see 200610). Unilateral polydactyly had been noted at birth.
In a family with Stickler syndrome (STL1; 108300), Ahmad et al. (1993) found a single-base mutation that converted codon 9 of the COL2A1 gene. (The amino acids of the alpha-1 chain were numbered with the standard convention in which the first amino acid in the triple-helical domain is numbered as +1 (Baldwin et al., 1989).) The mutation changed a CGA codon (arginine) to TGA (stop) codon. This mutation was located in exon 7. The PCR products contained both C and T, indicating that the patient was heterozygous for the mutation. The proband had been identified in a cleft palate clinic at the age of 1 year. He had severe myopia and was at the eighth percentile for height. Pelvic x-rays demonstrated small femoral heads with dumbbell-shaped enlargements of both ends of the femurs. Members in 3 generations and 4 sibships had severe myopia, often with other ocular manifestations.
Cole et al. (1993) found that a child with SED congenita (183900) was heterozygous for a G-to-A transition in exon 48 of the COL2A1 gene that resulted in the substitution of glycine-997 by serine in the triple helical domain of the type II collagen chain.
Winterpacht et al. (1993) demonstrated a 28-bp deletion spanning the 3-prime exon/intron boundary of exon 12 in a 2-year-old girl with Kniest dysplasia (156550). The mother presented with a milder phenotype consistent with the Stickler syndrome. She was shown to have mosaicism for the same deletion.
Wilkin et al. (1999) found this same mutation occurring at the junction between exon 12 and intron 12 of the COL2A1 gene in a patient with Kniest syndrome. The mutation deleted the splice donor site and was predicted to result in exon skipping in the mRNA encoded from the mutant allele. The female patient reported by Wilkin et al. (1999), their patient 4, had previously been reported by Siggers (1974) and Siggers et al. (1974), and by Maumenee and Traboulsi (1985). The diagnosis of Kniest dysplasia had been made at the age of 10.5 years. At that time, her height was 110.5 cm (height age 4 10/12 years). She had a flat and round face, prominent eyes with high myopia, flat bridge of the nose, with broad and prominent forehead, and a cleft uvula. Radiographs demonstrated severe platyspondyly, with greatest involvement of the dorsal spine. The superior and inferior endplates of the vertebral bodies were quite irregular, with spotted mineralization. There was considerable middorsal kyphosis and lumbar lordosis, as well as moderate scoliosis. The anterior-posterior diameters of the vertebral bodies appeared relatively wide, as did the interpedicular spaces. The limbs and hands had short bones, with shafts of normal to slightly diminished diameter, and greatly flared metaphyses and epiphyses. Ossification of the epiphyses was irregular and spotty, with some of the cartilaginous epiphyseal plates relatively wide, particularly at the distal radius and ulna. Wilkin et al. (1999) pointed out that the deletion in this case began with 7 nucleotides in exon 12 that duplicated 7 nucleotides (+3 through +9) of intron 12, creating the basis for homologous recombination with unequal crossing-over leading to deletion.
In a 16-year-old Finnish boy with spondyloepimetaphyseal dysplasia (184250), Vikkula et al. (1993) demonstrated a 1063G-A transition in exon 14 of the COL1A2 gene, which resulted in the conversion of gly154 to arg (G154R). This was a heterozygous de novo mutation which was not found in any other skeletal dysplasia patient studied in Finland.
Kaitila et al. (1996) found the same de novo heterozygous G154R mutation in an unrelated 26-year-old Finnish woman with spondyloepimetaphyseal dysplasia and provided follow-up on the patient reported by Vikkula et al. (1993). Both patients had been followed since the newborn period at Helsinki University Children's Hospital. The clinical phenotype was disproportionate short stature with varus/valgus deformities of the lower limbs requiring corrective osteotomies, and lumbar lordosis. The skeletal radiographs showed an evolution from short tubular bones, delayed epiphyseal development, and mild vertebral involvement to severe metaphyseal dysplasia with dappling irregularities, and hip 'dysplasia.' The metaphyseal abnormalities disappeared by adulthood.
Korkko et al. (1993) identified a substitution of aspartate for glycine at position 67 in the alpha-1 chain of type II collagen in a family in which affected members had early-onset cataracts, lattice degeneration of the retina, and retinal detachment without involvement of nonocular tissues. Comparison with previously reported mutations suggested to Korkko et al. (1993) that premature termination codons in the COL2A1 gene are a frequent cause of Stickler syndrome, but mutations in the COL2A1 gene that replace glycine codons with codons for a bulkier amino acid can produce a broad spectrum of disorders ranging from lethal chondrodysplasia to a syndrome involving only ocular tissues. Korkko et al. (1993) noted phenotypic similarity to the family described by Wagner (1938) (see 143200). Richards et al. (2006) suggested that the disorder in this family was more likely to be a predominantly ocular form of Stickler syndrome type I (see 609508).
In a family with Stickler syndrome (STL1; 108300) in members of 4 successive generations, Ritvaniemi et al. (1993) found a deletion of a T in the third base position of the codon CCT for proline at position 846 of the collagen II alpha-1 chain. The deletion of the T shifted the reading frame and generated premature termination. Ritvaniemi et al. (1993) stated that this was the fourth example of a premature termination codon causing Stickler syndrome.
In a 4-year-old girl with clinical and radiographic features typical of SED congenita (183900), Chan et al. (1993) found heterozygosity for a 2913C-T transition in exon 14, resulting in an arg789-to-cys (R789C) substitution. The mutation resulted in the loss of an MaeII cleavage site that was used to confirm the fact that the proband was heterozygous and that neither parent had the mutation. Type II collagen extracted from cartilage and from cultured chondrocytes was approximately one-third of the mutant type and secretion of molecules containing mutant chains was impaired. The thermal stability of the collagen extracted from cartilage was normal, however.
In a patient with SED congenita, Chan et al. (1995) identified the R789C mutation. The substitution of a cysteine for an arginine in the Y position of the gly-X-Y triplet is noteworthy because cysteine is not normally found in the triple-helical domain of type II collagen in any species (Kuivaniemi et al., 1997). A cysteine at this position provides the opportunity for disulfide bonds to form, thus disrupting the formation of collagen fibrils. Two other arg-to-cys mutations have been described in the COL2A1 gene: R519C (120140.0003), resulting in osteoarthritis with mild chondrodysplasia (604864), and R75C (120140.0018), resulting in spondyloepiphyseal dysplasia with precocious osteoarthritis (609162).
Tiller et al. (1993, 1995) demonstrated that cartilage from 3 patients with SEMD Strudwick (184250) contained both normal alpha-1(II) collagen chains and chains that were posttranslationally overmodified. Cyanogen bromide peptide analysis and protein microsequencing of type II collagen from 1 patient demonstrated an amino acid substitution, gly709-to-cys, in the abnormal alpha chains. Direct DNA sequencing showed heterozygosity for a GGC-to-TGC transversion at the last glycine codon of exon 39.
This mutation has also been designated arg275-to-cys (R275C) based on a different numbering system.
In a family living in the Chiloe Islands, Chile, Williams et al. (1993) demonstrated a heterozygous arg75-to-cys (R75C) mutation in the COL2A1 gene as the basis of spondyloepiphyseal dysplasia with shortened metacarpals and metatarsals, precocious osteoarthritis, and periarticular apatite-like calcific deposits. Seven individuals were involved in 3 generations of the family. Complete physical examination, anthropometric measurements, and radiographic studies of the spine and peripheral joints in 16 family members revealed that 7 had spondyloepiphyseal dysplasia tarda, brachydactyly, precocious osteoarthritis, and periarticular calcification, while 2 others had the same syndrome without brachydactyly (Reginato et al., 1994). The relationship of this type of SEDT to familial calcium pyrophosphate dihydrate deposition disease (118600) and idiopathic hip dysplasia, both endemic in Chiloe Islanders, required further investigation.
Hoornaert et al. (2007) performed targeted sequencing of exon 13 of the COL2A1 gene in patients with Czech dysplasia (609162) because of phenotypic similarities between individuals with this dysplasia and patients with the R75C mutation. They identified heterozygosity for the R75C mutation in 5 patients with Czech dysplasia, including 2 of the 4 original patients described with this disorder. All affected individuals had normal height, spondyloarthropathy, and short postaxial toes.
In an affected father, daughter, and son from a Japanese family with Czech dysplasia, Matsui et al. (2009) identified heterozygosity for the R275C mutation in the COL2A1 gene. The mutation was not found in the unaffected mother. The authors stated that this was the first reported family with Czech dysplasia that was not of European ancestry, and family history was consistent with de novo occurrence of the disease in the father.
Winterpacht et al. (1994) investigated the molecular defect in a girl with Kniest dysplasia (156550) whose father had a very mild form of spondyloepiphyseal dysplasia congenita (SEDC) with premature osteoarthrosis. The father was found to be a mosaic for a mutation that was present in nonmosaic state in the child: an A-to-G transition at the 3-prime end of intron 20 affecting the highly conserved AG dinucleotide of the acceptor splice site. The result was the utilization of a cryptic AG splice site located 18-bp downstream and a resulting in-frame deletion of 18 bp from the mRNA. This situation has similarities to that described in 120140.0012.
Wilkin et al. (1994) used SSCP to analyze an amplified genomic DNA fragment containing exon 12, under suspicion because of its deletion in a previously reported patient (120140.0012), from 7 individuals with Kniest dysplasia (156550). An abnormality was identified in 1 patient who was found on DNA sequence analysis to be heterozygous for a G-to-A transition that implied substitution of glycine-103 of the triple helical domain by aspartate. The mutation was not observed in DNA from either of the clinically unaffected parents. Protein microsequencing demonstrated expression of the abnormal allele in cartilage.
In a fetus with type II achondrogenesis (200610), Chan et al. (1995) described heterozygosity for a G-to-A transition at nucleotide 2853 in exon 441 of the COL2A1 gene, resulting in a gly769-to-ser substitution within the triple helical domain of the type II collagen chain. The result was complete absence of type II collagen in cartilage, which had a gelatinous composition. Types I and III collagens were the main species found in cartilage and synthesized by cultured chondrocytes along with cartilage type XI collagen (120280). Cultured chondrocytes produced a trace amount of type II collagen that was retained within the cells and not secreted. In situ hybridization of cartilage sections showed that the chondrocytes produced both type I and type II collagen mRNA. Chan et al. (1995) noted that the gly769 substitution is situated close to the mammalian collagenase cleavage site at gly775/leu776. The abnormality was detected by ultrasonography at 19 weeks of gestation when severe shortening of the limbs and trunk and marked edema around the neck was noted. The pregnancy was terminated at 20 weeks of gestation. External examination showed very short limbs, large head, short trunk, bulging abdomen, and edema of the head and neck. Radiographs, which were presented by Chan et al. (1995), showed very short tubular bones with metaphyseal expansion and cupping, absent ossification of the vertebrae and sacrum, small iliac wings with absent ossification of the pubis and ischium, and short ribs, but relatively normal ossification of the calvarium.
Mortier et al. (1995) examined a male fetus by ultrasound during the third trimester and observed polyhydramnios and severe short-limb dwarfism. The parents elected to induce delivery at 31 weeks of gestation and the neonate, who had achondrogenesis type II (200610), died soon after birth. There was severe shortening of the limbs and chest with distention of the abdomen. The head was relatively large and the neck appeared short. Radiographs showed absence of ossification of all the vertebral bodies. The chest appeared bell-shaped with mild shortening of the ribs. Anterior and posterior ends of the ribs were flared and cupped. The width of the iliac wings was increased and the greater sciatic notch was wide. The ischium and pubis were not ossified. All the long bones were markedly shortened with flared and cupped metaphyses. Electron microscopy showed inclusion bodies of dilated rough endoplasmic reticulum in chondrocytes and the presence of sparse collagen fibers in the cartilage matrix. Protein analysis of collagen from cartilage indicated posttranslational overmodification of the major cyanogen bromide peptides and suggested a mutation near the carboxyl terminus of the type II collagen molecule. Mortier et al. (1995) referred to reports of 3 other dominant mutations in the COL2A1 gene resulting in substitutions for triple helical glycine residues near the carboxy-terminal end of the alpha-1(II) chain and causing hypochondrogenesis. Mortier et al. (1995) demonstrated a single base change (G-to-C) that resulted in the substitution of glycine-691 by arginine in the type II collagen triple helical domain.
By direct sequencing of the COL2A1 gene, Ahmad et al. (1995) demonstrated that affected members of a family with Stickler syndrome (STL1; 108300) had a single base deletion in exon 50, resulting in a premature stop codon in exon 51 in the globular C-propeptide of the COL2A1 gene. The deletion involved a cytosine at position 92 in exon 50. Three generations were affected in the family. The proband was referred for cataract and total retinal detachment in 1 eye at the age of 3 years. Marked genu valgum, hyperextensibility of joints, cleft palate, and flattened facies were noted. Mild hearing loss was also documented. The father's left eye had been blind since the age of 8 years secondary to a detached retina. Retinal detachment on the right occurred at the age of 39 years. He also showed hyperextensibility of joints and some spinal changes. The proband's paternal uncle suffered detached left retina after diving into a swimming pool at age 15 years. Hyperextensibility of joints and loss of hearing in the left ear were noted at the age of 35 years. Hyperextensible joints were present in other relatives and Pierre Robin syndrome was noted in some.
In the original Minnesota kindred on the basis of which Stickler et al. (1965) defined the Stickler syndrome (STL1; 108300), Williams et al. (1996) identified a splice site mutation in the COL2A1 gene. They used conformational sensitive gel electrophoresis (SSGE) to screen for mutations in the entire gene. They noted a prominent heteroduplex in the PCR product from a region of the gene including exons 17 to 20. Direct sequencing of PCR-amplified genomic DNA identified an A-to-G transition at the -2 position at the 3-prime acceptor splice site of IVS17. Sequencing of DNA from affected and unaffected family members confirmed that the mutation segregated with the disease phenotype. RT-PCR analysis of poly(A)+ RNA demonstrated that the mutant allele utilized a cryptic splice site in exon 18 of the gene, eliminating 16 bp at the start of exon 18. This frameshift eventually resulted in a premature termination codon. Williams et al. (1996) stated that this was the first report of a splice site mutation in classical Stickler syndrome. They provided a satisfying historical context in which to view COL2A1 mutations in this disorder.
Spranger et al. (1997) demonstrated that the original patient reported by Kniest (1952) had a single base (G) deletion involving the GT dinucleotide of the start of intron 18 of the COL2A1 gene. From a review of the molecular defect found in other cases of this disorder, Spranger et al. (1997) concluded that the condition is caused by small in-frame deletions often due to exon skipping as a result of COL2A1 splice site mutations. Spranger et al. (1997) provided a useful follow-up on the original patient, then 50 years of age. She was severely handicapped with short stature, restricted joint mobility, and blindness, but was mentally alert and led an active life. Radiologic findings at the age of 4.5 years and 29 years were presented.
In a neonatal lethal form of Kniest dysplasia (156500), Weis et al. (1998) found deletion of 18 residues corresponding to exon 24 of the COL2A1 sequence. Sequence analysis of an amplified genomic DNA fragment identified a G-to-A transition in the +5 position of the splice donor consensus sequence of intron 24 in 1 allele. Cartilage matrix analysis showed that the abnormally short alpha-1(II) chain was present in collagen molecules that had become cross-linked into fibrils. It appeared that the normal and the short alpha-chains had combined to form heterotrimeric molecules in which the chains were in register in both directions from the deletion site, accommodated effectively by a loop out of the normal chain exon 24 domain. Such an accommodation, with potential overall shortening of the helical domain and hence misalignment of intermolecular relationships within fibrils, offers a common molecular mechanism by which a group of different mutations might act to produce the Kniest phenotype. The patient, an infant girl, was the product of a 37-week gestation and died of respiratory distress at 10 days of age. She had short limbs, clubfeet, cleft palate, midface hypoplasia, and narrow chest. X-rays showed flattened vertebral bodies with coronal clefts, slight shortening of the ribs, and dumbbell-shaped femurs.
See 120140.0017. In 2 unrelated patients with SEMD Strudwick (184250), Tiller et al. (1995) found a gly304-to-cys mutation and a gly292-to-val mutation in the COL2A1 gene.
See 120140.0027 and Tiller et al. (1995).
In an Afrikaner South African family with multiple epiphyseal dysplasia with myopia and conductive deafness (132450), Ballo et al. (1998) detected a heterozygous C-to-T transversion at nucleotide 2503 in exon 39 of the COL2A1 gene. This resulted in an arg-to-cys substitution at residue number 704, occurring at the X position of the Gly-X-Y motif of the collagen triple helix. Myopia and deafness characteristic of Stickler syndrome (108300) were present, with radiologic findings consistent with multiple epiphyseal dysplasia (MED). COL2A1 mutations causing Stickler syndrome have resulted in premature termination codons, while mutations causing spondyloepiphyseal dysplasia were glycine alterations or arg-to-cys substitutions at the Y position of the Gly-X-Y unit. Ballo et al. (1998) stated that this mutation could represent the first report of a nontermination COL2A1 mutation in Stickler syndrome type 1, or the first report of a COL2A1 defect in an MED phenotype.
Zabel et al. (1996) described a 5-bp duplication in exon 51 of the COL2A1 gene, leading to a stop codon, in a patient with a distinct phenotype labeled spondyloperipheral dysplasia (271700). The mutation was present in heterozygous state and the patient was sporadic (new mutation). The patient, a girl, was born to healthy, nonconsanguineous parents and was 45 cm at birth. A skeletal dysplasia was suspected because of rhizomelic shortening of the arms and legs. X-ray findings at 7 months of age suggested SED congenita. At the age of 14 years the patient was 127.4 cm tall with short, broad fingers and very short toes II-V. Additional findings were a slightly hypoplastic midface with depressed nasal bridge, severe myopia, short neck and trunk, accentuated lumbar lordosis, and limited extension of the elbow joints. Short metacarpals were impressive in the hand x-rays, and very short toes II-V were impressive in the photograph of the feet. The 5-bp duplication was the first to be located at the C-terminal outside the helical domain of COL2A1. It seemed to affect helix formation and produced changes of chondrocyte morphology, collagen type II fibril structure, and cartilage matrix composition.
Sobetzko et al. (2000) described a newborn infant with an unusual combination of syndactylies, macrocephaly, and severe skeletal dysplasia. A history of digital anomalies in the father and grandfather led to the diagnosis of dominantly inherited Greig cephalopolysyndactyly syndrome (GCPS; 175700). Having explained the digital findings and macrocephaly, the skeletal changes were thought to fit best congenital SED (183900). Molecular analysis confirmed the presence of 2 dominant mutations in the infant: a GLI3 mutation (E543X; 165240.0010), which was present also in the father and grandfather, and a de novo COL2A1 mutation leading to an gly973-to-arg amino acid substitution. Thus, this boy combined the Greig syndrome with a severe form of SED. The diagnostic difficulties posed by the combination of 2 genetic disorders and the usefulness of molecular diagnostics were well illustrated.
Freddi et al. (2000) described a novel strategy for screening families with type I Stickler syndrome (STL1; 108300) due to nonsense mutations in the COL2A1 gene, using a modified RNA-based protein truncation test. To overcome the problem of the unavailability of collagen II-producing cartilage cells, they performed RT-PCR on the illegitimate transcripts of accessible cells (lymphoblasts and fibroblasts), which were preincubated with cycloheximide to prevent nonsense mutation-induced mRNA decay. The 5 overlapping RT-PCR fragments covering the COL2A1 coding region were then transcribed and translated in vitro to identify smaller truncated protein products resulting from a premature stop codon. Using this method, Freddi et al. (2000) screened a 4-generation family with Stickler syndrome and identified a protein-truncating mutation that was present in all affected individuals. Targeted sequencing identified the mutation as a G-to-A transition at the +1 position of the 5-prime splice donor site of intron 25. The mutation led to the activation of a cryptic splice site 8 bp upstream, causing aberrant mRNA splicing and a translational frameshift that introduced a premature stop codon. Mutant mRNA was undetectable without cycloheximide protection, demonstrating that the mutant mRNA was subjected to nonsense-mediated mRNA decay.
Richards et al. (2000) observed a recurrent arg365-to-cys (R365C) mutation of the COL2A1 gene in 2 unrelated sporadic cases of Stickler syndrome (STL1; 108300). The mutation was located in the X position of the Gly-X-Y triple helical region and resulted in the membranous vitreous anomaly associated with haploinsufficiency.
Richards et al. (2000) observed a leu467-to-phe (L467F) mutation of the COL2A1 gene in a family with Stickler syndrome (STL1; 108300) which produced an unusual 'afibrillar' vitreous gel devoid of all normal lamellar structure. Systemic involvement was mild, with many family members lacking joint laxity or radiologic abnormality, hearing loss, midface hypoplasia, abnormal nasal development, and midline clefting. Richards et al. (2005) referred to the phenotype in this family as an atypical form of Stickler syndrome/dominant rhegmatogenous retinal detachment (609508). They noted that the amino acid substitution arose from a 20996C-T transition.
Unger et al. (2001) reported a child with double heterozygosity for pseudoachondroplasia (177170), resulting from a mutation in the COMP gene (600310.0014) and spondyloepiphyseal dysplasia congenita (183900), resulting from a thr1370-to-met mutation in the COL2A1 gene. The child inherited pseudoachondroplasia from his mother and spondyloepiphyseal dysplasia congenita from his father. He had clinical and radiographic findings that were more severe than those in either disorder alone.
Gupta et al. (2002) examined a large French Canadian kindred originally described by Alexander and Shea (1965) as representing Wagner disease (143200). In affected individuals, they found a novel frameshift mutation (4274del2bp) in exon 2 leading to early truncation of the COL2A1 protein (cys57 to stop; C57X). The mutation arose in an exon that is selectively present in vitreous collagen mRNAs, but absent in cartilage mRNAs through tissue-specific alternate splicing. The authors concluded that the selective absence of exon 2 in cartilage explained why this family did not manifest the progressive spondyloarthropathy of Stickler syndrome (108300) that is a more common result of mutations in COL2A1.
Richards et al. (2006) suggested that the disorder in this family was more likely to be a predominantly ocular form of Stickler syndrome type I (see 609508).
Richards et al. (2002) described a large family with dominantly inherited rhegmatogenous retinal detachment, premature arthropathy, and phalangeal epiphyseal dysplasia resulting in brachydactyly (VPED; 619248). Linkage to the COL2A1 gene was demonstrated, and mutation analysis identified a change at codon 1105 in exon 52 from GGC (gly) to GAC (asp) (G1105D) in the C-propeptide region of the molecule. The gly-to-asp change occurred in a region that is highly conserved in all fibrillar collagen molecules. The resulting phenotype did not fit easily with preexisting subgroups of the type II collagenopathies.
In 2 successive pregnancies of a healthy, nonconsanguineous young couple, Faivre et al. (2004) observed lethal achondrogenesis type II (200610). Heterozygosity for a 1340G-A transition in exon 22 of the COL2A1 gene resulting in a gly316-to-asp (G316D) amino acid substitution was identified in the second fetus. The mutation was not found in the parents. Faivre et al. (2004) hypothesized germline mosaicism in 1 of the parents as the explanation for the recurrence of this autosomal dominant disorder.
In a sporadic case of the Torrance type of platyspondylic skeletal dysplasia (151210) delivered stillborn at 34 weeks' gestation, Nishimura et al. (2004) identified a de novo heterozygous 4172A-G transition in exon 53 of the COL2A1 gene, resulting in a tyr1391-to-cys (Y1391C) mutation affecting the C-propeptide region of the protein.
Hoornaert et al. (2007) identified a heterozygous 4172A-G transition of the COL2A1 gene in a girl originally diagnosed with Czech dysplasia (case III of Kozlowski et al., 2004). The patient had significant disproportionate short stature (-4.55 standard deviation at age 14) and short toes. Hoornaert et al. (2007) suggested that this patient has spondyloperipheral dysplasia (271700).
In a sporadic case of the Torrance type of platyspondylic skeletal dysplasia (151210), Nishimura et al. (2004) identified a de novo 4-bp deletion in exon 54 of the COL2A1 gene, 4413delAGGG, resulting in a frameshift with a premature stop at codon 1480. The phenotype, as indicated by radiologic manifestations during the neonatal period, evolved into that of Kniest-like dysplasia (see 156550) in childhood; the patient, 5 years of age at the time of report, survived respiratory problems in infancy.
In 2 patients with spondyloperipheral dysplasia (271700), Zankl et al. (2004) identified mutations in the COL2A1 gene. The first patient had a heterozygous 1-bp deletion at nucleotide 4337 in exon 52, resulting in a frameshift at codon 1446 and a premature stop codon 25 amino acids downstream. The second patient had a truncating mutation in exon 51 (see 120140.0042). Neither mutation was present in the patients' parents or in 100 control chromosomes. Both patients had clubfeet, midface hypoplasia, early-onset high grade myopia, platyspondyly, epiphyseal dysplasia, and brachydactyly E-like changes developing in childhood. The authors noted that the phenotype was remarkably similar to that described by Zabel et al. (1996) (see 120140.0030).
In a patient with spondyloperipheral dysplasia (271700), Zankl et al. (2004) identified a heterozygous 4314C-A transversion in exon 51 of the COL2A1 gene, resulting in a cys1438-to-ter (C1438X) substitution. See 120140.0041.
In 2 families with autosomal dominant avascular necrosis of the femoral head (ANFH1; 608805), Liu et al. (2005) identified a G-to-A transition in exon 50 of the COL2A1 gene, predicted to lead to the replacement of glycine with serine at codon 1170 (G1170S) in a Gly-X-Y repeat of type II collagen. The mutant allele occurred on a different haplotype background in each of the 2 families.
Miyamoto et al. (2007) identified the same heterozygous 3508G-A mutation in affected members of a Japanese family with an autosomal dominant disorder manifesting as Legg-Calve-Perthes disease (LCPD; 150600).
In a family with autosomal dominant avascular necrosis of the femoral head (ANFH1; 608805), Liu et al. (2005) identified a G-to-A transition in exon 33 of the COL2A1 gene, causing a glycine-to-serine change at codon 717 (G717S).
In a patient with sporadic Stickler syndrome (STL1; 108300), Wilkin et al. (2000) identified a C-to-T transition in the COL2A1 gene, resulting in an arg453-to-ter (R453X) substitution. The patient had cleft palate, sensorineural hearing loss, joint laxity, high myopia, vitreoretinal degeneration, and retinal breaks and detachments.
In affected members of a family with no systemic characteristics of Stickler syndrome but dominantly inherited rhegmatogenous retinal detachment or retinal tears (609508), Go et al. (2003) identified the R453X mutation, which they noted was in exon 30 (Wilkin et al. (2000) had placed the mutation in exon 28). They noted that previously reported predominantly ocular Stickler syndrome cases had been associated with protein-truncating mutations in exon 2, an exon subject to alternative splicing.
In affected members of a family with dominantly inherited rhegmatogenous retinal detachment (609508) and no systemic clinical signs (skeletal, orofacial, or auditory) usually associated with Stickler syndrome (108300), Richards et al. (2005) identified a 10838G-A transition in exon 15 of the COL2A1 gene, resulting in a gly118-to-arg (G118R) substitution.
In monozygotic twin girls with SEMD Strudwick (184250), Sulko et al. (2005) identified heterozygosity for a 79A-G transition in exon 41 of the COL2A1 gene, resulting in an arg792-to-gly (R792G) substitution. The mutation was not detected in the unaffected parents or in 90 controls.
In a 22-year-old Japanese female with Stickler syndrome (STL1; 108300), who had a clinical diagnosis of otospondylomegaepiphyseal dysplasia (see 215150), Miyamoto et al. (2005) identified a splice acceptor site mutation within intron 10 (709-2A-G) of the COL2A1 gene. The mutation was predicted to cause skipping of exon 11, which was presumed to cause an in-frame deletion of the triple helical region of the COL2A1 product.
In a family with the predominantly ocular form of type I Stickler syndrome (609508), Richards et al. (2006) found that the donor splice site of intron 51 showed a change from GT to GC. Using splicing reporter constructs, they demonstrated that normal transcripts could be produced from this mutant allele. Some GC donor splice sites exist naturally in the human genome (Thanaraj and Clark, 2001). Whether there is a difference in the efficiency of normal splicing from the mutant GC allele between cartilage and ocular tissue was unknown. However, Richards et al. (2006) observed that not all cells transfected with the mutant minigene were capable of normal processing of the mutant mRNA, so tissue-specific missplicing may be one explanation for the predominantly ocular phenotype in this family. An alternative explanation is that vitreous development (which is rapid, with the secondary vitreous complete by 12 weeks' gestation) is more susceptible to a reduction in the level of type II collagen than is cartilage development, in which the extracellular matrix has longer to develop.
In a family with the predominantly ocular form of Stickler syndrome type I (609508), Richards et al. (2006) found a nonsense mutation, trp47 to ter (W47X), resulting from a 141G-A transition in exon 2 of the COL2A1 gene. They observed 2 other examples of predominantly ocular Stickler syndrome due to mutations in the alternatively spliced exon 2. One other mutation causing this phenotype was located at the donor splice site of IVS51 (120140.0049).
In 2 unrelated patients with nonsyndromic ocular Stickler syndrome (609508), McAlinden et al. (2008) identified a heterozygous 192C-A transversion in exon 2 of the COL2A1 gene, resulting in a cys64-to-ter (C64X) substitution. In vitro studies using a minigene construct indicated that the C64X, C57Y (120140.0052), and W47X (120140.0050) mutations resulted in a splicing pattern change and a decreased ratio of IIA:IIB mRNA. The findings suggested that the mutations were present in functional cis regulatory elements in exon 2 that are important in regulating the mechanism of alternative splicing of this exon. McAlinden et al. (2008) postulated that the mutations did not result in nonsense-mediated decay and haploinsufficiency, but rather an altered mRNA splice ratio with effects limited to the eye. Absence of an extraocular phenotype in Stickler syndrome patients with mutations in exon 2 of COL2A1 may be due to sufficient production of isoform IIB by nonsense-mediated altered splicing. Since isoform IIA is expressed in adult ocular vitreous, the ocular phenotype may be due to inadequate amounts of isoform IIA in the mature eye.
In a patient with nonsyndromic ocular Stickler syndrome (609508), McAlinden et al. (2008) identified a heterozygous 170G-A transition in exon 2 of the COL2A1 gene, resulting in a cys57-to-tyr (C57Y) substitution.
In 3 fetuses with lethal achondrogenesis type II (200610) born to a healthy, nonconsanguineous young couple, Forzano et al. (2007) identified heterozygosity for a 1037G-T transversion in exon 3 of the COL2A1 gene resulting in a gly346-to-val (G346V) substitution. An earlier born fetus had also had achondrogenesis type II. The father's blood DNA harbored a low mutation signal consistent with mosaicism. Additional DNA analyses of the father's fibroblasts, hair roots, buccal smear, and urine revealed weak mosaicism in all tissues. Forzano et al. (2007) stated that this was the first case of proven somatic mosaicism for a COL2A1 mutation that led to a lethal skeletal dysplasia in 4 offspring.
In a 40-year-old man who was diagnosed with avascular necrosis of the femoral head (ANFH1; 608805) at 18 years of age, Kannu et al. (2011) identified heterozygosity for a 4148C-T transition in exon 51 of the COL2A1 gene, resulting in a thr1383-to-met (T1383M) substitution within the highly conserved C-propeptide region. The mutation was not found in unaffected family members or 150 age-, sex-, and ethnicity-matched controls. The patient had a normal skeletal survey, other than bilateral hip degeneration; he had no facial dysmorphism, and ophthalmologic and audiologic examinations were normal.
In a mother and daughter and an unrelated Korean boy with the Stanescu type of spondyloepiphyseal dysplasia (SEDSTN; 616583), Jurgens et al. (2015) identified heterozygosity for a c.619G-A transition (c.619G-A, NM_001844.4) in the COL2A1 gene, resulting in a gly207-to-arg (G207R) substitution at a conserved residue. The mutation was not present in the unaffected maternal grandmother from the first family; DNA from the maternal grandfather was unavailable. In the Korean family, the mutation was not present in either of the unaffected parents, indicating de novo occurrence in the proband.
In 6 affected members of a 3-generation family with the Stanescu type of spondyloepiphyseal dysplasia (SEDSTN; 616583), Hammarsjo et al. (2015) identified heterozygosity for a c.3655G-C transversion (c.3655G-C, NM_001844.4) in exon 51 of the COL2A1 gene, resulting in an asp1219-to-his (D1219H) substitution at a highly conserved residue within the carboxy-propeptide of the alpha I (II) procollagen chain. The mutation segregated with disease in the family and was not found in 249 exomes from a local ethnically mixed population or in the ExAC, 1000 Genomes Project, dbSNP (build 137), ESP6500, or Leiden Open Variation databases.
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