HGNC Approved Gene Symbol: COL10A1
SNOMEDCT: 29248006;
Cytogenetic location: 6q22.1 Genomic coordinates (GRCh38): 6:116,118,909-116,217,144 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q22.1 | Metaphyseal chondrodysplasia, Schmid type | 156500 | Autosomal dominant | 3 |
Type X is a short-chain minor collagen of cartilage (Schmid and Linsenmayer, 1985). During development and growth of long bones, chondrocytes pass sequentially through a proliferative, a hypertrophic and a degenerative stage, each characterized by a particular set of collagen types. Proliferative (stage I) chondrocytes synthesize type II collagen as the major collagen and types IX and XI as the minor collagens. Hypertrophic (stage II) chondrocytes localized in the columnar, calcifying cartilage are characterized by the synthesis of types X and II collagen.
Kirsch and von der Mark (1991) isolated human type X collagen from fetal human growth plate cartilage and purified it to homogeneity. They raised an antiserum against the purified protein and used the antibody to show the distribution of type X collagen in fetal human growth plate cartilage and in the calcifying zone of fetal human sternum. Possible involvement of the COL10A1 gene in chondrodysplasias and other disorders of cartilage such as osteoarthrosis was suggested.
Thomas et al. (1991) reported the complete primary sequence of type X collagen. Collagen X is a homotrimer containing 3 identical chains with a relative molecular mass of 59,000. The triple helical domain is approximately half the size of that in collagen of types I, II, and III. The localization of collagen X and its transient expression at sites of calcification suggests that it is associated with events in the later stages of endochondral bone formation. Collagen X possesses striking structural similarities to collagen VIII (120251), another short-chain collagen found predominantly in Descemet membrane, the specialized basement membrane synthesized by corneal endothelial cells. Two exons encode the complete primary translation product, which consists of a putative signal-peptide sequence (18 amino acids), an N-terminal noncollagenous domain (38 amino acids), a triple helix (463 amino acids), and a C-terminal noncollagenous domain (161 amino acids).
Zheng et al. (2003) identified multiple functional RUNX2 (600211)-binding sites within the promoter region of the human, mouse, and chicken COL10A1 genes. In transgenic mouse cells, Runx2 contributed to the transactivation of the Col10a1 promoter. Also, decreased Col10a1 expression and altered chondrocyte hypertrophy were observed in Runx2 heterozygous mice, whereas Col10a1 was barely detectable in Runx2 null mice. Zheng et al. (2003) concluded that COL10A1 is a direct transcriptional target of RUNX2 during chondrogenesis.
Thomas et al. (1991) determined that collagen X is encoded by 2 exons of 169 bp and 2,940 bp, which are separated by a 3,200-bp intron.
Ho et al. (2007) noted that the COL10A1 gene contains 3 exons with a noncoding first exon.
With consensus primers based on the nucleotide sequence of the chicken type X collagen gene, Apte et al. (1991) used PCR with human genomic DNA as a template to isolate a 289-bp fragment for part of the carboxyl non-triple helical domain of the human gene. Using the PCR clone as a probe for in situ hybridization of human metaphase chromosome spreads and for Southern analysis of a panel of human-hamster somatic cell hybrid DNAs, they assigned the COL10A1 locus to 6q21-q22. Thomas et al. (1991) likewise assigned COL10A1 to 6q21-q22.3 by a combination of somatic cell hybrid screening and in situ hybridization. Apte et al. (1992) demonstrated that this gene is located on mouse chromosome 10.
Using PCR and SSCP, Sweetman et al. (1992) identified 7 sequence changes in the coding region of the COL10A1 gene. Six of these were shown to be polymorphic in nature and were used to demonstrate discordant segregation between the COL10A1 locus and both achondroplasia (100800) and pseudoachondroplasia (177170). The seventh sequence change resulted in a val-to-met substitution in the C-terminal domain of the molecule and was identified only in 2 persons with hypochondroplasia (146000) from a single family. Segregation analysis in this family was inconclusive; thus the significance of the substitution remained uncertain.
Warman et al. (1993) proved that mutation in the COL10A1 gene is responsible for Schmid metaphyseal chondrodysplasia (MCDS; 156500). A number of COL10A1 mutations have been identified in patients with MCDS; each is within the C-terminal noncollagenous (NC1) domain and it has been suggested that the phenotype is the result of the inability of the mutant polypeptide to initiate trimer formation (Warman et al., 1993; McIntosh et al. (1994, 1995)).
Wallis et al. (1996) reviewed the 21 known mutations in the COL10A1 gene that have been associated with the Schmid type of metaphyseal chondrodysplasia and noted that all occur in the region of COL10A1 encoding the C-terminal NC1 domain. They contended that the restricted distribution of COL10A1 mutations causing MCDS argues against haploinsufficiency being the mutation mechanism in this disorder.
Warman et al. (1993) and Wallis et al. (1996) found no mutations in the COL10A1 gene in patients with other types of metaphyseal chondrodysplasia. Ikegawa et al. (1997) found 2 de novo missense mutations in the N-terminal globular domain of the type X collagen gene. Previously reported mutations had all involved the C-terminal globular domain. The clinical phenotype for MCDS was typical in these Japanese patients.
Kuivaniemi et al. (1997) tabulated 17 different mutations in the COL10A1 gene that had been identified in patients with MCDS.
Spondylometaphyseal dysplasia (SMD) comprises a heterogeneous group of heritable skeletal dysplasias characterized by modifications of the vertebral bodies of the spine and metaphyses of the tubular bones. Ikegawa et al. (1998) examined the entire coding region of COL10A1 in a search for mutations in 5 unrelated patients with SMD because Schmid metaphyseal chondrodysplasia shows significant phenotypic overlap with SMD, and because transgenic mice carrying deletions in type X collagen show SMD phenotypes (Jacenko et al., 1993). They found a heterozygous missense mutation (120110.0016) cosegregating with the disease phenotype in 1 SMD family. The 1 patient in whom the COL10A1 mutation was found had been described by Hasegawa et al. (1994) as having a novel type of SMD called the Japanese type. Four other unrelated Japanese patients who were studied were sporadic instances of SMD. Two of them were thought to have the Kozlowski type (184252); one had the corner fracture type (184255), and one had an unspecified form of SMD. No mutation was found in these 4 cases.
By molecular modeling of the C-terminal NC1 domain of mutated recombinant COL10A1, Marks et al. (1999) determined that many of the mutations that result in MCDS are localized to 2 specific regions of the folded monomeric NC1 domain. By mutation analysis, they showed that NC1 domains containing the tyr598-to-asp (Y598D; 120110.0002) and ser600-to-pro (S600P; 120110.0018) mutations retained the ability to form trimers, although these trimers showed less thermal stability than wildtype molecules.
Wilson et al. (2002) analyzed the expression and degradation of COL10A1 mutations in patient cartilage tissue and in transfected cells. They found that COL10A1 carrying the Y598D mutation or a frameshift mutation resulted in proteins that were fully degraded, resulting in 50% less functional collagen X within patient growth plates. Wilson et al. (2002) determined that the mutant chains were capable of triple helix formation. When transfected into osteosarcoma cells, however, the mutants were expressed at the mRNA level, but the protein was not secreted. Inhibitor studies indicated that the mutant collagens remained associated with the endoplasmic reticulum and were degraded by both the proteasome and lysosome degradation pathways.
Chan et al. (2001) determined that COL10A1 harboring mutations in or near the N-terminal signal sequence, such as gly18 to arg (G18R; 120110.0012), result in chains that can associate into trimers, but the signal peptide is not removed and the trimers cannot form a triple helix. The mutant chains remain anchored to the membrane of microsomes and are not secreted.
In 2 MCDS patients with COL10A1 nonsense mutations, trp611 to ter (120110.0019) and tyr632 to ter (120110.0015), Bateman et al. (2003) showed that the mutated alleles underwent complete nonsense-mediated mRNA decay (NMD) in cartilage, but not in lymphoblasts or bone cells. The authors suggested that novel RNA surveillance mechanisms may exist in cartilage, and that tissue specificity of NMD could be of importance in understanding the molecular pathology of nonsense mutations.
Makitie et al. (2005) reported 10 patients with MCDS and COL10A1 mutations in whom the most characteristic radiographic findings were found in the proximal femoral metaphysis, which showed metaphyseal irregularity, coxa vara, and a vertical growth plate in all the patients. Makitie et al. (2005) concluded that type X collagen plays a key role in femoral neck development and may be an important determinant of its length, width, and neck-shaft angle.
Chan et al. (1998) demonstrated lack of mutant RNA in the growth plate cartilage of a patient with MCDS and suggested that haploinsufficiency was the molecular basis of MCDS. Gregory et al. (2000), however, demonstrated the presence of both mutant and normal mRNA in the growth plate of a patient with MCDS and suggested that a dominant-negative effect was more likely to be the molecular basis of MCDS.
Bateman et al. (2005) stated that 33 unique heterozygous mutations in the COL10A1 gene had been described in 36 cases of Schmid metaphyseal chondrodysplasia and that these were about equally divided between missense mutations and mutations that introduced premature termination signals. These mutations were clustered (33 of 36 patients) in the 3-prime region of exon 3, which codes for the C-terminal NC1 trimerization domain. In the case of COL10A1 missense mutations, a common consequence appeared to be a disruption of collagen X trimerization and secretion, with consequent intracellular degradation. COL10A1 nonsense mutations in cartilage tissue lead to removal of the mutant RNA by nonsense-mediated mRNA decay (NMD). Thus, for both classes of mutations, functional haploinsufficiency is the most probable cause of the clinical phenotype in MCDS.
In a 13-year-old boy with MCDS, Ho et al. (2007) identified heterozygosity for a nonsense mutation in COL10A1 (Y663X; 120110.0020). Approximately 50% of mutant Y663X mRNA was translated into truncated alpha-1(X) chains that were misfolded, unable to assemble into trimers, and interfered with the assembly of normal alpha-1(X) chains into trimers.
Jacenko et al. (1993) produced a spondylometaphyseal dysplasia in mice by a transgenic dominant-negative mutation in type X collagen. Of interest, Rosati et al. (1994) observed normal long bone growth and development in mice expressing no type X collagen. This finding supports the contention that Schmid metaphyseal chondrodysplasia is the result of a dominant-negative effect of mutant collagen polypeptide and not the deficiency of normal type X collagen as suggested previously (Warman et al., 1993; McIntosh et al. (1994, 1995))
Gress and Jacenko (2000) showed that transgenic and knockout mice with inactivated Col10a1 manifest variable phenotypes reflecting certain skeletohematopoietic defects. A subset of the knockout mice (approximately 11%) died 3 weeks after birth, and others continued to exhibit defects with age. Defects included erythrocyte predominance in marrow, reduced spleen and thymus size, altered B and T lymphocyte development, aberrant endochondral ossification, and dwarfism.
Nielsen et al. (2000) showed that a dominant form of skeletal dysplasia in domestic pigs is due to a gly590-to-arg missense mutation in the COL10A1 gene, and thus is a valid animal model of Schmid metaphyseal chondrodysplasia, which it resembles on radiologic and histologic grounds.
Similarities between Schmid metaphyseal chondrodysplasia and short stature in various dog breeds suggested COL10A1 as a candidate for canine skeletal dysplasia. Young et al. (2006) reported the sequencing of the exons and promoter region of the COL10A1 gene in dog breeds fixed for a specific type of skeletal dysplasia known as chondrodysplasia, breeds that segregate the skeletal dysplasia phenotype, and control dogs of normal stature. They could find no evidence that the skeletal dysplasia phenotype in these dog breeds is related to COL10A1.
Ho et al. (2007) studied transgenic mice bearing the equivalent of a human 1859delC frameshift mutation (120110.0005), which displayed typical characteristics of MCDS including disproportionate shortening of limbs and early onset coxa vara. The degree of expansion of the hypertrophic zones was noted to be transgene dosage-dependent, being most severe in mice homozygous for the transgene, and chondrocytes in the lower region of the expanded hypertrophic zone expressed markers uncharacteristic of hypertrophic chondrocytes, indicating that differentiation was disrupted. Misfolded mutant alpha-1(X) chains were retained within the endoplasmic reticulum (ER) of hypertrophic chondrocytes, activating the unfolded protein response. Ho et al. (2007) suggested that a gain-of-function effect, linked to the activation of the ER-stress response and altered chondrocyte differentiation, was a possible molecular pathogenetic mechanism for MCDS.
Nonsense-mediated decay (NMD) is a eukaryotic cellular RNA surveillance and quality control mechanism that degrades mRNA containing premature stop codons (nonsense mutations) that otherwise might exert a deleterious effect by the production of dysfunctional truncated proteins. Nonsense mutations in type X collagen causing Schmid metaphyseal chondrodysplasia are localized in a region toward the 3-prime end of the last exon (exon 3) and result in mRNA decay, in contrast to most other genes in which terminal-exon nonsense mutations are resistant to NMD. To explore the mechanism of last-exon mRNA decay of COL10A1, Tan et al. (2008) introduced nonsense mutations into the mouse Col10a1 gene and expressed these in a hypertrophic-chondrocyte cell line. They demonstrated that mRNA decay is spatially restricted to mutations occurring in a 3-prime region of the exon 3 coding sequence, and this region corresponds to that in which human mutations have been described. This localization of mRNA decay competency suggested that a downstream region, such as the 3-prime untranslated region (UTR), may play a role in specifying decay of mutant Col10a1 mRNA containing nonsense mutations. Tan et al. (2008) found that deleting any of the 3 conserved sequence regions within the 3-prime UTR prevented mutant mRNA decay. These data suggested that the 3-prime UTR participates in collagen X last-exon mRNA decay and that overall 3-prime UTR configuration, rather than specific linear sequence motifs, may be important in specifying decay of COL10A1 mRNA containing nonsense mutations.
Forouhan et al. (2018) generated mice homozygous or heterozygous for the Col10a1 mutation Y632X (120110.0015), which causes MCDS in humans. In contrast with the human MCDS patient heterozygous for Y632X, who expressed only the normal allele, Y632X mRNA in mice had the same stability as wildtype mRNA and did not undergo NMD. Regardless, both heterozygous and homozygous mutant mice grew slower than wildtype and had a robust MCDS phenotype. Mutant mice of either genotype had increased ER stress, and the Y632X protein induced a significant unfolded protein response. Histologic characterization revealed disrupted hypertrophic differentiation in growth plates of mice expressing the truncated mutant protein. Treatment of mutant mice with carbamazepine significantly reduced disease severity and ER stress and improved hypertrophic differentiation in growth plates.
In a Mormon kindred with autosomal dominant Schmid metaphyseal chondrodysplasia (MCDS; 156500) reported by Stephens (1943) as an example of achondroplasia and studied by Caffey and Christensen (1963), Warman et al. (1993) identified a 13-bp deletion starting with basepair 1856 in heterozygous state in the COL10A1 gene. The mutation produced a frameshift that altered the highly conserved C-terminal domain of the alpha-1(X) chain and reduced the length of the polypeptide by 9 residues.
Using PCR and SSCP techniques to analyze the coding and upstream promoter regions of the COL10A1 gene, Wallis et al. (1994) identified heterozygosity for a single basepair transition that led to substitution of the highly conserved amino acid residue tyrosine at position 598 by aspartic acid (Y598D) in 5 affected members of a family with Schmid type metaphyseal chondrodysplasia (MCDS; 156500). The mutation was located within the carboxyl-terminal domain of the type X collagen chains.
In a sporadic case of Schmid type metaphyseal chondrodysplasia (MCDS; 156500), Wallis et al. (1994) identified a 1-bp transition in the COL10A1 gene, resulting in a substitution of leucine-614 by proline (L614P). The mutation was located within the carboxyl-terminal domain of the type X collagen chains.
Using PCR and SSCP analyses to examine the coding region of the COL10A1 gene, McIntosh et al. (1994) identified a single bp T-to-C transition that led to the substitution of the cysteine residue at position 591 by arginine (C591R) in a single, sporadic case of Schmid metaphyseal chondrodysplasia (MCDS; 156500). This residue is conserved across species and may be essential for intermolecular disulfide bridge formation prior to triple helix formation. The proband's unaffected mother proved to be somatic mosaic for the C591R mutation.
In a sporadic case of Schmid metaphyseal chondrodysplasia (MCDS; 156500), McIntosh et al. (1994) identified a single base deletion of a cytosine residue (1856delC) in a span of 4 cytosines in exon 3 of the COL10A1 gene by PCR and SSCP analysis, which was predicted to result in frameshift and a premature termination codon after amino acid 620. Ho et al. (2007) referred to this mutation as 1859delC.
McIntosh et al. (1994) identified a 2-bp deletion in a sporadic case of Schmid metaphyseal chondrodysplasia (MCDS; 156500) which would be predicted to introduce a premature stop codon after amino acid 664 in COL10A1.
Heteroduplex analysis of PCR-amplified genomic DNA identified a 10-bp deletion in COL10A1 starting from nucleotide 1867 that segregated with Schmid metaphyseal chondrodysplasia (MCDS; 156500) in a 5-generation pedigree (Dharmavaram et al., 1994). The deletion overlaps that identified by Warman et al. (1993) (120110.0001) and gives rise to the same downstream protein sequence.
Another 2-bp deletion was identified in a sporadic case of Schmid metaphyseal chondrodysplasia (MCDS; 156500) by McIntosh et al. (1995), coincidentally at the same position in COL10A1 as the deletion of the single base at 1856 in 120110.0005 and the start of the 13-bp deletion described previously (120110.0001).
A tyr628-to-ter (Y628X) mutation of COL10A1 was identified in a sporadic case of Schmid metaphyseal chondrodysplasia (MCDAS; 156500) by McIntosh et al. (1995).
Using PCR and SSCP, McIntosh et al. (1995) identified a trp651-to-ter mutation (W651X) of the COL10A1 gene in a sporadic case of Schmid metaphyseal chondrodysplasia (MCDS; 156500).
In a Japanese family with Schmid metaphyseal chondrodysplasia (MCDS; 156500), Pokharel et al. (1995) found that affected members had a T-to-C transition at nucleotide 1951 of COL10A1 that resulted in replacement of tryptophan by arginine at residue 651 (W651R). This novel mutation seemed to have the same impact on bone development as the W651X mutation (120110.0010).
In a Japanese patient with typical Schmid metaphyseal chondrodysplasia (MCDS; 156500), Ikegawa et al. (1997) found a heterozygous 52G-A transition of COL10A1 that caused replacement of a glycine residue by arginine at codon 18 (G18R).
In a Japanese patient with typical Schmid metaphyseal chondrodysplasia (MCDS; 156500), Ikegawa et al. (1997) found a heterozygous 53G-A transition of COL10A1 that caused replacement of a glycine residue by glutamic acid at codon 18 (G18E).
In 3 members of a family affected by Schmid metaphyseal chondrodysplasia (MCDS; 156500), Stratakis et al. (1996) identified a T-to-C transition at nucleotide 2011 of the COL10A1 gene, resulting in a ser671-to-pro (S671P) substitution. The mother in this family, a 36-year-old woman with a height of 140 cm, had mild bilateral coxa vara. Her 2 sons, who had been delivered vaginally, had normal birth length and weight. Both had normal early development but developed leg bowing when they started walking.
Chan et al. (1998) obtained growth plate cartilage from a patient with Schmid metaphyseal chondrodysplasia (MCDS; 156500), determined the type of collagen X mutation, and analyzed the expression of mutant and normal type X collagen mRNA and protein. The mutation was found to be a single nucleotide substitution that changed the tyr632 codon (TAC) to a stop codon (TAA). However, analysis of the expression of the normal and mutant allele transcripts in growth plate cartilage by reverse transcription PCR, restriction enzyme mapping, and a single nucleotide primer extension assay demonstrated that only normal mRNA was present. The lack of mutant mRNA is most likely the result of nonsense-mediated mRNA decay, a common fate of transcripts carrying premature termination mutations. Furthermore, no mutant protein was detected by immunoblotting cartilage extracts. The data indicated that a functionally null allele leading to type X collagen haploinsufficiency is the molecular basis of MCDS in this patient.
Bateman et al. (2003) demonstrated that Y632X mutant mRNA underwent nonsense-mediated decay in cartilage tissue but not in noncartilage cells.
In affected members of a family with the Schmid type of metaphyseal chondrodysplasia (MCDS; 156500), Bonaventure et al. (1995) identified heterozygosity for a 1784G-A transition in the COL10A1 gene, resulting in a gly595-to-glu (G595E) substitution.
Hasegawa et al. (1994) described a Japanese family with a form of autosomal dominant spondylometaphyseal dysplasia that they termed the Japanese type (see 156500). In affected members of this family, Ikegawa et al. (1998) identified the G595E mutation.
In a Japanese girl with the clinical diagnosis of sporadic Schmid metaphyseal chondrodysplasia (MCDS; 156500), Sawai et al. (1998) demonstrated a tyr597-to-cys (Y597C) mutation in the COL10A1 gene. Both parents lacked the mutation.
In a patient with Schmid metaphyseal chondrodysplasia (MCDS; 156500), Gregory et al. (2000) identified a T-to-C transition at nucleotide 1894, which was predicted to cause a ser600-to-pro (S600P) substitution in the NC1 domain of type X collagen. Gregory et al. (2000) further demonstrated that mRNA transcribed from both the wildtype and mutant COL10A1 alleles was available for translation in growth plate cartilage from the patient. Gregory et al. (2000) concluded that the molecular mechanism in MCDS was likely to be dominant interference of normal type X collagen by MCDS mutant chains rather than haploinsufficiency, as was suggested by Chan et al. (1998) (120100.0015).
In a proband with Schmid metaphyseal chondrodysplasia (MCDS; 156500), Bateman et al. (2003) identified a G-to-A transition at position 1832 of the COL10A1 DNA that resulted in a trp611-to-ter (W611X) amino acid change. The authors demonstrated that while mutant mRNA underwent nonsense-mediated decay in cartilage tissue, it was not subjected to nonsense-mediated decay in noncartilage cells.
In a 13-year-old boy with Schmid metaphyseal chondrodysplasia (MCDS; 156500), Ho et al. (2007) identified heterozygosity for a 1989C-G transversion in exon 3 of the COL10A1 gene, resulting in a tyr663-to-ter (Y663X) substitution and a truncated protein lacking the last 18 amino acids of the NC1 domain. Comparison of normal to mutant mRNA and genomic DNA showed that approximately 50% of mutant mRNA was degraded and the rest was translated into truncated alpha-1(X) chains. In vitro studies demonstrated that the truncated collagen X chains were misfolded, unable to assemble into trimers, and interfered with the assembly of normal alpha-1(X) chains into trimers. An iliac crest cartilage biopsy from the proband showed that the hypertrophic zone of the iliac growth plate was expanded and that the cellular architecture of the hypertrophic zone was disorganized.
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