Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: COL4A1
SNOMEDCT: 1173997008, 247123003, 702428000;
Cytogenetic location: 13q34 Genomic coordinates (GRCh38): 13:110,148,963-110,307,157 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 13q34 | ?Retinal arteries, tortuosity of | 180000 | Autosomal dominant | 3 |
| {Hemorrhage, intracerebral, susceptibility to} | 614519 | 3 | ||
| Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps | 611773 | Autosomal dominant | 3 | |
| Brain small vessel disease with or without ocular anomalies | 175780 | Autosomal dominant | 3 | |
| Microangiopathy and leukoencephalopathy, pontine, autosomal dominant | 618564 | Autosomal dominant | 3 |
The COL4A1 gene encodes the alpha-1 subunit of collagen type IV. Types I, II, and III collagen, the so-called interstitial collagens, are in many ways distinct from basement membrane collagen. Type IV collagen does not form ordered fibrillar structures; rather, a meshwork is formed by 4 molecules held together at the ends. Both disulfide and typical lysyl-derived collagen crosslinks are involved (Kuhn, 1982). Crouch et al. (1980) presented evidence that type IV procollagen contains 2 distinct chains. The collagen IV molecule is a heterotrimer of 2 alpha-1 chains and 1 alpha-2 chain (Mayne et al., 1984). The alpha-2 chain is encoded at a distinct locus (COL4A2; 120090).
Pihlajaniemi et al. (1985) reported the isolation and characterization of cDNA clones corresponding to the alpha-1 chain of collagen IV.
Poschl et al. (1988) isolated and sequenced a 2.2-kb genomic fragment that contained the 5-prime terminal exons of both COL4A1 and COL4A2. The 2 genes were found to be arranged in opposite directions, head-to-head, separated only by 127 bp. The connecting segment apparently contained promoters of both genes as indicated by the existence of typical sequence motifs. Poschl et al. (1988) interpreted the findings as suggesting that the 2 genes have a common, bidirectional promoter.
Soininen et al. (1988) found that the COL4A1 and COL4A2 genes are encoded on opposite DNA strands from loci that are so closely located that they may be separated by as little as 42 basepairs. This was the first description of 2 structural genes from a complex organism coding for 2 polypeptide chains of the same protein molecule but having overlapping 5-prime flanking regions. Many of the genes of simple organisms with small genomes are encoded on opposite DNA strands so that the genes either overlap or 1 gene is nested within another gene.
Tsonis and Goetinck (1988) pointed out structural relatedness of the Drosophila homeotic gene 'spalt' and the alpha-1 chain of type IV collagen. This may reflect a role of extracellular products of homeotic genes in cell-to-cell interactions. Burbelo et al. (1988) found a similar situation in the mouse where the collagen genes exist in a head-to-head arrangement on opposite strands separated by 130 basepairs; they are regulated by a bidirectional promoter located between the 2 genes working in concert with an enhancer located in the first intron of the COL4A1 gene.
Plaisier et al. (2010) stated that the COL4A1 gene contains 52 coding exons.
To elucidate the chemical nature of bonds in the alpha-1-alpha-2-alpha-1 collagen IV network, Vanacore et al. (2009) used Fourier-transform ion cyclotron resonance mass spectrometry and nuclear magnetic resonance spectroscopy to show that a sulfilimine bond (-S=N-) crosslinks hydroxylysine-211 and methionine-93 of adjoining promoters, a bond not previously found in biomolecules. This bond, the nitrogen analog of a sulfoxide, appears to have arisen at the divergence of sponge and cnidaria, an adaptation of the extracellular matrix in response to mechanical stress in metazoan evolution.
Using a cloned gene as a probe on Southern blots of DNA from a panel of interspecies somatic cell hybrids, Solomon et al. (1985) assigned one of the collagen IV genes, COL4A1, to chromosome 13.
Pihlajaniemi et al. (1985) used dual-laser sorted chromosomes and spot-blot analysis to assign genomic DNA sequences coding for COL4A1 to chromosome 13. By in situ hybridization, Boyd et al. (1986) localized the gene to the end of the long arm of chromosome 13. Southern and spot-blot hybridization showed that these genomic sequences were present only once per haploid genome.
Emanuel et al. (1986) assigned COL4A1 to the telomeric region of 13q (13q34) by in situ hybridization. Bowcock et al. (1987) found that the COL4A1 locus is linked to D13S3, which in turn has been assigned to 13q33-q34 by in situ hybridization. They found a maximum lod score of 16.5 at theta = 0.01.
Griffin et al. (1987) showed by in situ hybridization and Southern blot analysis of DNA from somatic cell hybrids that the COL4A2 gene is also on the distal long arm of chromosome 13, apparently closely linked to the alpha-1(IV) gene. By means of pulsed-field gel electrophoresis (PFGE) and infrequently cutting restriction enzymes, Cutting et al. (1987) showed that the COL4A1 and COL4A2 genes are separated by no more than 400 kb. Cutting et al. (1988) demonstrated that the 2 genes are located within a 340-kb region, with the 3-prime end of COL4A2 and the 5-prime region of COL4A1 separated by at least 100 kb but not more than 160 kb.
Using RFLPs identified within the 2 genes, Hebert et al. (1987) also showed that COL4A1 and COL4A2 are closely linked. Bowcock et al. (1988) found that the COL4A1 and COL4A2 genes are linked, with a maximum likelihood estimate of recombination of 0.028 at a lod score of 19.98. This and the lack of linkage disequilibrium are inconsistent with relatively high recombination between the 2 loci--higher than expected for 2 genes that lie within 650 kb of each other.
Koizumi et al. (1995) used interspecific and intersubspecific mapping panels to locate the Col4a1 gene to the centromeric region of mouse chromosome 8. COL4A2 (120090) and coagulation factor X (F10; 613872) mapped to the same region, thus defining a new region of homology of synteny between mouse chromosome 8 and human chromosome 13.
By microarray analysis, Jun et al. (2001) demonstrated expression of the COL4A1 gene in human donor corneas.
Human noncollagenous domain-1 of the alpha-1 chain of type IV collagen, alpha-1(IV)NC1, or arresten, is derived from the carboxy terminal of type IV collagen. It was shown to inhibit angiogenesis and tumor growth in vivo (Maeshima et al., 2000).
In both Drosophila embryo and ovary, Wang et al. (2008) showed that type IV collagen extracellular matrix proteins bind Dpp, a BMP signaling molecule, and regulate its signaling. The authors provided evidence that the interaction between Dpp and type IV collagen augments Dpp signaling in the embryo by promoting gradient formation, yet it restricts the signaling range in the ovary through sequestration of the Dpp ligand. Wang et al. (2008) concluded that their results identified a critical function of type IV collagens in modulating Dpp in the extracellular space during Drosophila development. On the basis of their findings that human type IV collagen binds BMP4 (112262), Wang et al. (2008) predicted that this role of type IV collagens is conserved.
Brain Small Vessel Disease 1 with or without Ocular Anomalies
Gould et al. (2005) assessed 2 families in which members were affected by brain small vessel disease (BSVD1; 175780), manifest as porencephaly on brain imaging, for mutations in the COL4A1 gene. The first family, previously reported by Smit et al. (1984), had a gly1236-to-arg substitution (G236R; 120130.0001); the second family, previously reported by Aguglia et al. (2004), had a gly749-to-ser substitution (G749S; 120130.0002). Both mutations changed conserved glycine residues within the Gly-X-Y repeats in the triple helical domain.
Small vessel disease of the brain underlies 20 to 30% of ischemic strokes and a larger proportion of intracerebral hemorrhages. Gould et al. (2006) showed that a mutation in the mouse Col4a1 gene predisposes both newborn and adult mice to intracerebral hemorrhage. Phenotypic similarities between Col4a1 mutant mice and a French family with brain small vessel disease prompted Gould et al. (2006) to assess the family for COL4A1 mutations. Sequence analysis revealed a missense mutation (G562E; 120130.0003) that segregated with the disease and was not observed in 196 chromosomes from unaffected French persons.
In 3 unrelated Dutch families segregating for porencephaly caused by perinatal vascular accidents, Breedveld et al. (2006) identified 3 different mutations in the COL4A1 gene. Two were missense mutations of glycine residues predicted to result in abnormal collagen IV assembly (G1130D, 120130.0005; G1423R, 120130.0006), and 1 mutation was predicted to abolish the traditional COL4A1 start codon (M1L; 120130.0004). The last mutation was also present in an asymptomatic obligate carrier with white matter abnormalities on brain magnetic resonance imaging.
Sibon et al. (2007) identified a heterozygous mutation in the COL4A1 gene (G720D; 120130.0010) in affected members of a French Canadian family with brain small vessel disease associated with leukoencephalopathy and Axenfeld-Rieger ocular anomalies.
In a mother and daughter with brain hemorrhage, periventricular leukoencephalopathy, and ocular anomalies, Coupry et al. (2010) identified heterozygosity for a missense mutation in the COL4A1 gene (G755R; 120130.0020).
In 5 affected children from 4 families with recurrent stroke, infantile hemiplegia/spastic quadriplegia, infantile spasms, and ocular anomalies, Shah et al. (2012) identified heterozygosity for 4 different missense mutations in the COL4A1 gene, including the G755R substitution in 1 boy and a G773R substitution (120130.0021) in 2 sibs.
Weng et al. (2012) demonstrated in in vitro cellular expression assays that COL4A1 mutations reported in patients with brain small vessel disease (G562E, 120130.0003; G720D, 120130.0010) caused a significant reduction in the ratio of extracellular to intracellular COL4A1 compared to control, suggesting that intracellular accumulation of the mutant protein underlies the disorder.
In affected members of 2 unrelated families, of Belgian and Dutch descent, with brain small vessel disease with hemorrhage, Lemmens et al. (2013) identified 2 different heterozygous truncating mutations in the COL4A1 gene (120130.0018 and 120130.0019). Analysis of patient cells showed nonsense-mediated mRNA decay and a reduction of COL4A1 protein expression, indicating that the mutations caused haploinsufficiency rather than a dominant-negative effect.
In a large 4-generation family with multiple ocular anomalies, brain hemorrhage, and extensive leukoencephalopathy mapping to chromosome 13q, Rodahl et al. (2013) identified a heterozygous missense mutation in the COL4A1 gene (N1627K; 120130.0022) that segregated with disease and was not found in 185 controls.
Yoneda et al. (2013) identified heterozygous COL4A1 mutations in 10 (16.4%) of 61 patients with porencephaly on brain imaging who did not have mutations in the COL4A2 gene and in 5 (50%) of 10 additional patients with schizencephaly on brain imaging (see, e.g., G1326R; 120130.0017). Nine mutations occurred at highly conserved glycine residues in the gly-X-Y repeat of the collagen triple-helical domain, and Yoneda et al. (2013) noted that impairment of the collagen IV heterotrimer assembly caused by mutant COL4A1 is a common pathologic mechanism. The findings also demonstrated that COL4A1 mutations can cause both porencephaly and schizencephaly, supporting the same pathologic mechanism for these 2 conditions.
In a Hispanic brother and sister and an Indian girl with microphthalmia and other ocular anomalies, Deml et al. (2014) identified heterozygosity for the G773R mutation and a G708R mutation (120130.0023) in COL4A1, respectively. Other than mild learning disability in the sibs, these patients had no neurologic symptoms. Deml et al. (2014) stated that microphthalmia had been reported in 4 of 97 previously published cases of COL4A1-associated cerebrovascular disease.
Meuwissen et al. (2015) reported the experience of the Erasmus University Medical Center in sequencing the COL4A1 and COL4A2 genes in 183 index patients, mostly with cerebral hemorrhage or porencephaly, between 2005 and 2013. In total, 21 COL4A1 and 3 COL4A2 mutations were identified, mostly in children with porencephaly or other patterns of parenchymal hemorrhage, with a high de novo mutation rate of 40% (10/24).
Abe et al. (2017) identified heterozygosity for a missense mutation in the COL4A1 gene (G1035V; 120130.0024) in a boy with schizencephaly, renovascular hypertension, and retinal arteriosclerosis. From the age of 9 years, he had repeated alveolar hemorrhage from a tracheostoma, from which he died at age 11.
Hereditary Angiopathy with Nephropathy, Aneurysms, and Muscle Cramps
Plaisier et al. (2007) characterized the renal and extrarenal phenotypes of subjects from 3 families who had autosomal dominant hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC; 611773), which they proposed to represent a syndrome. They performed linkage studies involving microsatellite markers flanking the COL4A1-COL4A2 locus followed by sequence analysis of COL4A1 cDNA extracted from skin-fibroblast specimens from the subjects. By this approach, Plaisier et al. (2007) identified 3 closely located glycine mutations in exons 24 and 25 of the COL4A1 gene (120130.0007, 120130.0008, 120130.0009). The 3 affected glycine residues are located in the collagenous domain at sites that are highly conserved. The clinical renal manifestations of the HANAC syndrome in these families included hematuria and bilateral large cysts. Histologic analysis revealed complex basement membrane defects in kidney and skin. The systemic angiopathy of the HANAC syndrome appeared to affect both small vessels and large arteries.
In affected members of 3 families exhibiting key features of HANAC, Plaisier et al. (2010) identified 3 different heterozygous missense mutations in the COL4A1 gene (120130.0012-120130.0014, respectively). The authors noted that all 6 mutations associated with the HANAC phenotype to that time were localized within the CB3(IV) integrin-binding fragment of COL4A1, suggesting that abnormal cell-type IV collagen interactions may underlie the systemic defects observed in this syndrome.
Weng et al. (2012) demonstrated in in vitro cellular expression assays that COL4A1 mutations reported in patients with HANAC (G498V, 120130.0007; G528E, 120130.0009) caused a significant reduction in the ratio of extracellular to intracellular COL4A1 compared to control, suggesting that intracellular accumulation of the mutant protein underlies the disorder. However, G519R (120130.0008) did not cause a significant accumulation, which may have reflected different activity in vitro compared to in vivo.
Susceptibility to Intracerebral Hemorrhage
In 2 of 96 patients with adult-onset hemorrhagic stroke, Weng et al. (2012) identified different heterozygous mutations in the COL4A1 gene (120130.0015 and 120130.0016). The COL4A1 gene was chosen for study because mutation in this gene can cause rare familial forms of cerebrovascular disease. In vitro cellular studies showed that both mutant proteins were retained intracellularly and impaired normal COL4A1 secretion.
Tortuosity of Retinal Arteries
In a Spanish father and 2 daughters with tortuosity of the retinal arteries and retinal hemorrhage (180000), but no muscle cramps or renal or brain anomalies, Zenteno et al. (2014) identified heterozygosity for the G510R mutation in the COL4A1 gene (120130.0013) that was previously detected by Plaisier et al. (2010) in affected members of a French family with HANAC syndrome (611773). Zenteno et al. (2014) suggested that environmental factors and/or other genetic modifiers may influence the phenotypic expression and extent of organ involvement in COL4A1-related disease.
Autosomal Dominant Pontine Microangiopathy and Leukoencephalopathy
In 6 affected members from a large French family (F1) with autosomal dominant pontine microangiopathy and leukoencephalopathy (PADMAL; 618564), Verdura et al. (2016) identified a heterozygous c.*35C-A transversion in the 3-prime UTR of the COL4A1 gene (120130.0025). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the 1000 Genomes Project, Exome Variant Server, or ExAC databases. Targeted sequencing of this region of the gene in 202 unrelated probands with a similar disorder identified 2 more heterozygous mutations in the same region of the gene (120130.0026-120130.0027) in affected members of 5 additional families with a similar disorder, including a German family previously reported by Hagel et al. (2004). In vitro functional expression studies in HEK293 cells showed that all the mutations interfered with miRNA29 (see 610782) binding and resulted in increased expression of COL4A1 compared to wildtype. Levels of COL4A1 mRNA were increased in patient fibroblasts compared to controls.
In affected members of a large 5-generation Swedish family with PADMAL, (Sourander and Walinder, 1977), Siitonen et al. (2017) identified a heterozygous c.*32G-A transition in the 3-prime UTR of the COL4A1 gene (120130.0028). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression studies in HEK293 cells showed that the mutation interfered with miRNA29 binding and resulted in increased expression of COL4A1 compared to wildtype. The findings confirmed the results of Verdura et al. (2016) and defined a specific phenotype caused by perturbations of the cerebrovascular matrisome that results in recurrent lacunar infarcts.
Gould et al. (2005) identified and characterized a novel mouse mutant generated by random mutagenesis with severe perinatal cerebral hemorrhage. In addition to cerebral hemorrhage, mutant mice were smaller than control littermates and had multiple pleiotropic phenotypes including ocular abnormalities, mild renal abnormalities, and reduced fertility that appeared to be influenced by genetic context. Homozygous mutant mice were not viable after midembryogenesis, and about 50% of heterozygous mice died within a day of birth. Mutant mice carried a splice site mutation causing excision of exon 40 of the Col4a1 gene. COL4A1 gives strength to basement membranes. Gould et al. (2005) found that compared with controls, mice heterozygous for the Col4a1 exon 40 deletion had uneven basement membranes with inconsistent density and focal disruptions. The major site of hemorrhage was the brain.
Van Agtmael et al. (2005) identified an allelic series of 3 induced dominant mouse mutants with missense mutations in the Col4a1 gene: Svc (small with vacuolar cataracts), Raw (retinal arteriolar wiring), and Bru (bruised). Bru heterozygotes showed ocular anterior segment defects (see 107250) similar to Axenfeld-Rieger anomaly, including iris defects, corneal opacities, vacuolar cataracts, iris/corneal adhesions, buphthalmos, and optic nerve cupping, as well as retinal detachment. Bru mice also developed a renal glomerulopathy. The Raw mice showed a silvery appearance of the retinal arterioles. The observed phenotypes were associated with generalized basement membrane defects, but showed a high degree of tissue-specific variability. All mutations affected crucial glycine residues in a Gly-Xaa-Yaa repeat in the central collagen domain.
Gould et al. (2007) studied C57BL6/J mice with a Col4a1 splice site mutation that causes absence of exon 40 from mature transcript. Homozygotes were not viable, and all surviving heterozygotes had clinically obvious anterior segment defects with some combination of buphthalmos, corneal opacification, pigment dispersion, iridocorneal synechiae, cataract, persistence of tunica vasculosa lentis, abnormal iris vasculature, and optic nerve hypoplasia. When C57BL6/J mice were crossed with mice from 2 other inbred strains, 129/SvEvTac and CAST/EiJ, the F1 progeny were nearly indistinguishable from wildtype, with only mild enlargement of the anterior chamber. Using appropriate crosses and genetic mapping, Gould et al. (2007) identified a single dominant locus on mouse chromosome 1 that segregated with rescue of ASOD; marker analysis revealed a 38-Mb critical interval between markers D1Mit211 and D1Mit303 that strongly associated with the rescued phenotype and likely contains the modifier gene or genes.
Mao et al. (2015) tested the effects of a Col4a1 mutation in 2 different genetic backgrounds in mice to compare how genetic context influences ocular dysgenesis, intraocular pressure (IOP), and progression to glaucoma. Col4a1 mutant mice maintained on a C57BL/6J (B6) background were crossed to either 129S6/SvEvTac or CAST/EiJ and the F1 progeny analyzed. The CAST/EiJ inbred strain had a relatively uniform and profound suppression on the effects of the Col4a1 mutation, and mutant CASTB6F1 mice were only mildly affected. In contrast, mutant 129B6F1 mice had more variable and severe anterior segment dysgenesis and IOP dysregulation that were associated with glaucomatous signs including lost or damaged retinal ganglion cell axons and excavation of the optic nerve head.
Van Agtmael et al. (2010) showed that animals with a Col4a1 missense mutation (Col4a1+/Raw) display focal detachment of the endothelium from the media and age-dependent defects in vascular function including a reduced response to norepinephrine. Age-dependent hypersensitivity to acetylcholine was abolished by inhibition of nitric oxide synthase (NOS) activity, indicating that Col4a1 mutations affected vasorelaxation mediated by endothelium-derived nitric oxide. These defects were associated with a reduction in basal NOS activity and the development of heightened nitric oxide sensitivity of the smooth muscle. The vascular function defects were physiologically relevant as they maintained, in part, the hypotension in mutant animals, which was primarily associated with a reduced red blood cell volume due to a reduction in red blood cell number, rather than defects in kidney function. The deposition of collagen type IV in the basement membrane was defective, and the mutation was found to lead to activation of the unfolded protein response.
Kuo et al. (2014) compared the phenotypic effects of 8 different mutations in the Col4a1 gene in mice: 6 of the mutations affected glycine residues in the triple-helix-forming domain, 1 was a missense mutation (S1582P) in the globular NC1 domain, and 1 was a deletion. All mutations caused ocular dysgenesis, variable brain malformations, and myopathy, and the allelic heterogeneity influenced the extent and severity of abnormalities, thus contributing to phenotypic variability. The S1582P variant consistently showed the mildest phenotype. There appeared to be a positional effect, such that glycine mutations closer to the C terminus tended to result in increased intracellular levels of the protein, whereas those closer to the N terminus tended to result in lower intracellular protein levels; however, this did not affect clinical severity. Conditions that promoted protein folding, such as reduced temperature and 4-phenylbutyrate, ameliorated abnormal intracellular accumulation of mutant Col4a1.
Mao et al. (2021) crossed mutant Col4a1 mice with a deletion of exon 41 with C57BL/6J (B6) mice, resulting in F1 progeny that had reduced ocular anterior segment dysgenesis (ASD), intracerebral hemorrhage (ICH) and skeletal myopathy. Additional back-crossing identified a single locus on mouse chromosome 1, which the authors named modifier of Gould syndrome-1 (MoGS1). Of 4 genes in the MoGS1 region that are expressed in the eye, FN1 (135600) was considered the most likely candidate due to its known binding sites for type IV collagen.
The article by Sudhakar et al. (2005) suggesting that arresten is a potential therapeutic candidate for targeting tumor angiogenesis was retracted because the Office of Research Integrity reported falsified data in the article.
In a Dutch family with brain small vessel disease-1 (BSVD1; 175780), originally described by Smit et al. (1984), Gould et al. (2005) identified a G-to-A transition at nucleotide 3706 of the COL4A1 gene, resulting in a gly-to-arg substitution at codon 1236 (G1236R). The mutation segregated with the phenotype in the family and was not identified in 192 Dutch control chromosomes. The mutation disrupts the conserved glycine residues within the Gly-X-Y repeats in the triple helix domain.
In an Italian family with brain small vessel disease-1 (BSVD1; 175780), originally described by Aguglia et al. (2004), Gould et al. (2005) identified a G-to-A transition at nucleotide 2245 of the COL4A1 gene, resulting in a gly-to-ser substitution at codon 749 (G749S). This mutation segregated with the phenotype in the family and was not present in 192 ethnically and geographically matched Italian control chromosomes. The mutation changes a conserved glycine residue within the Gly-X-Y repeats in the triple helix domain.
In a French family with brain small vessel disease-1 (BSVD1; 175780), Gould et al. (2006) found a heterozygous 1769G-A transition in exon 25 of the COL4A1 gene that segregated with the disease. The mutation resulted in a missense change, gly562-to-glu (G562E), in the triple helix domain of the protein. Glycine residues are highly conserved within the triple helix domain of collagen type IV alpha-1, and mutations in codons encoding glycine are pathogenic in multiple species.
In members of a Dutch family (family A) with brain small vessel disease-1 (BSVD1; 175780), Breedveld et al. (2006) described an A-to-T transversion of the first nucleotide in exon 1 of the COL4A1 gene that was predicted to eliminate the ATG start codon, resulting in no protein or in a translation initiation site moving upstream or downstream. Affected members were present in 3 generations, with 1 asymptomatic carrier. In 1 individual neglect for the right arm was noted at the age of 5 months and by the age of 15 months a right-sided hemiplegia was diagnosed. Two males in the first generation were known to have congenital hemiplegia. The family had previously been reported by Mancini et al. (2004).
In a Dutch family (family B) with brain small vessel disease-1 (BSVD1; 175780) in a father and his 2 daughters, Breedveld et al. (2006) found that these affected individuals had a 3389G-A transition in exon 39 of the COL4A1 gene that resulted in a gly-to-asp substitution at codon 1130 (G1130D). The father had been examined at the age of 6 years because of unexplained mild left-sided hemiparesis. The family had previously been reported by Mancini et al. (2004).
In a Dutch family (family C) with brain small vessel disease-1 (BSVD1; 175780) in which a 2-year-old boy and his mother had congenital right hemiplegia and normal cognition, Breedveld et al. (2006) found that both had a 4267G-C transversion in exon 48 of the COL4A1 gene, predicted to cause a gly1423-to-arg mutation (G1423R).
In a French Caucasian family in which affected members in 4 generations had a syndrome of angiopathy, nephropathy, aneurysms, and muscle cramps (HANAC; 611773), Plaisier et al. (2007) detected a heterozygous mutation in exon 24 of the COL4A1 gene: 1493G-T, resulting in a gly498-to-val substitution (G498V). All affected subjects presented with microscopic hematuria, muscle cramps with elevated creatine kinase levels, and bilateral retinal arteriolar tortuosity that caused repeated retinal hemorrhages. Gross hematuria occurred in 3 subjects; supraventricular cardiac arrhythmia in 3 subjects; and Raynaud phenomenon in 5 subjects. Small bilateral renal cysts were demonstrated by CT in 3 subjects. Brain MRI revealed white matter abnormalities and dilated microvascular spaces in 4 subjects. Aneurysms affecting the intracranial segment of the right internal carotid artery were found in 3 subjects. Electron microscopic examination of kidney biopsy specimens showed alterations of the basement membranes of the Bowman capsule, tubules, and interstitial capillaries. While focal interruptions of the basement membrane were seen in interstitial capillaries, the glomerular basement membrane had a normal appearance and thickness. Similar alterations of the basement membrane, including duplications, were seen in the skin at the dermoepidermal junction.
In a family in which members of 3 successive generations had hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC; 611773), Plaisier et al. (2007) detected a heterozygous mutation in exon 25 of the COL4A1 gene: 1555G-A, resulting in a gly519-to-arg substitution (G519R). In this family the affected subjects presented with bilateral retinal arteriolar tortuosity, which caused hemorrhages in 3 subjects. Bilateral renal cysts and decreased glomerular filtration rate were demonstrated. One individual had elevated creatine kinase levels but no muscle symptoms. A single aneurysm of the right internal carotid artery and changes of leukoencephalopathy were demonstrated.
In a woman with hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC; 611773), Plaisier et al. (2007) detected a heterozygous 1583G-A transition in exon 25 of the COL4A1 gene that resulted in a gly528-to-glu (G528E) substitution. The woman's father had apparently been affected with the same disorder. The proband had leukoencephalopathy, cerebral aneurysms, Raynaud phenomenon, cardiac arrhythmia, and bilateral large kidney cysts.
In 5 affected members of a French Canadian family with brain small vessel disease associated with diffuse periventricular leukoencephalopathy and ocular anomalies (BSVD1; 175780), Sibon et al. (2007) identified a heterozygous 2159G-A transition in exon 29 of the COL4A1 gene, resulting in a gly720-to-asp (G720D) substitution within the triple helix domain. The mutation was not present in 200 control chromosomes. All patients had diffuse leukoencephalopathy and ocular defects, including congenital cataract, microcornea, and Axenfeld-Rieger anomaly. Other variable features included increased ocular pressure, retinal detachment, and stroke-like episodes. One patient had infantile hemiparesis and left paraventricular porencephaly. Retinal vessel tortuosity was not observed.
In 2 Dutch sibs born prematurely with brain small vessel disease-1 with ocular anomalies (BSVD1; 175780), de Vries et al. (2009) identified a heterozygous 4738G-C transversion in exon 50 of the COL4A1 gene, resulting in a gly1580-to-arg (G1580G) substitution in one of the Gly-X-Y repeats of the protein. Their mother also carried the mutation, which was not present in 300 control chromosomes. Possible antenatal trauma occurred only in the first infant at 23 weeks' gestational age. Routine brain imaging in both infants at birth showed resolving intracranial hemorrhages in the left lateral ventricles with an ipsilateral porencephalic cyst and small cystic lesions in the periventricular white matter of the contralateral hemisphere. At age 18 months, the older child had right-sided hemiplegia, strabismus associated with a quadrant hemianopsia, but no cataract or tortuosity of the retinal arteries. His developmental quotient was 68. At age 9 months, the second child had increased tone of the lower limbs and strabismus. Brain MRI of the mother showed mild ventricular dilatation and multiple hyperintense lesions in the periventricular white matter of both hemispheres, but no dilated perivascular spaces or evidence of microbleed. Her father had a history of transient ischemic attacks and died at age 52 years after a severe intracranial hemorrhage. De Vries et al. (2009) suggested that COL4A1 mutation carriers are at risk for intracranial hemorrhage from fetal life into adulthood and that antenatal intracerebral hemorrhage can lead to porencephaly in the newborn.
In affected members of a German family exhibiting key features of the HANAC syndrome (611773), previously reported by Gekeler et al. (2006), Plaisier et al. (2010) identified heterozygosity for a 1493G-T transversion in exon 24 of the COL4A1 gene, resulting in a gly498-to-arg (G498R) substitution at a highly conserved residue in the CB3(IV) region of the collagenous domain. All 3 patients had retinal arteriolar tortuosity, but none had the muscle cramps or renal disease characteristic of HANAC patients, although 1 daughter had a history of transient microhematuria. Brain involvement in this family included a history of stroke in the father, migraine headaches reported by 1 daughter, and leukoencephalopathy found on brain imaging in the other daughter.
Hereditary Angiopathy with Nephropathy, Aneurysms, and Muscle Cramps
In a father and 2 daughters from a French family exhibiting key features of the HANAC syndrome (611773), Plaisier et al. (2010) identified heterozygosity for a 1528G-A transition in exon 24 of the COL4A1 gene, resulting in a gly510-to-arg (G510R) substitution at a highly conserved residue in the CB3(IV) region of the collagenous domain. All 3 patients had retinal arteriolar tortuosity and elevated CPK levels, and both daughters reported muscle cramps; none had renal cysts or hematuria, and only the father had a reduced glomerular filtration rate. Brain imaging was normal in this family, although 1 daughter had migraine headaches.
Tortuosity of Retinal Arteries
In a Spanish father and 2 daughters with tortuosity of the retinal arteries and retinal hemorrhage (RATOR; 180000), who did not have muscle cramps, neurologic or cardiovascular symptoms, or renal or brain anomalies, Zenteno et al. (2014) identified heterozygosity for the G510R mutation in the COL4A1 gene. The mutation, which segregated with disease in the family, was not found in 200 ethnically matched control alleles or in 8,600 exomes in the NHLBI Exome Variant Server database. Zenteno et al. (2014) suggested that environmental factors and/or other genetic modifiers may influence the phenotypic expression and extent of organ involvement in COL4A1-related disease.
In affected members of a 3-generation French family exhibiting key features of the HANAC syndrome (611773), Plaisier et al. (2010) identified heterozygosity for a 1573GG-TT transversion in exon 25 of the COL4A1 gene, resulting in a gly525-to-leu (G525L) substitution at a highly conserved residue in the CB3(IV) region of the collagenous domain. All 5 patients had retinal arteriolar tortuosity, muscle cramps, and CPK levels ranging from 2.5 to 3.6 times the upper limit of normal. Renal cysts were present in 2 patients, 1 of whom also had a decreased glomerular filtration rate. The 4 patients who underwent brain imaging all showed leukoencephalopathy, and 1 had multiple aneurysms of the right internal carotid artery; in addition, 1 patient had a history of migraine headaches, and a 34-year-old female had a history of stroke. Three of the 5 patients exhibited Raynaud phenomena.
In 1 of 96 unrelated patients with intracerebral hemorrhage (ICH; 614519), Weng et al. (2012) identified a heterozygous 1055C-T transition in exon 19 of the COL4A1 gene, resulting in a pro352-to-leu (P352L) substitution at the highly conserved Y position of a Gly-Xaa-Yaa repeat within the triple helix-forming domain of the protein. The mutation was not found in 290 control chromosomes. In vitro functional expression studies showed that the mutant protein was retained intracellularly and was not secreted normally. The patient was a 73-year-old Hispanic woman who was on oral warfarin for aortic valve replacement and had some evidence of cerebral amyloid angiopathy.
In 1 of 96 unrelated patients with intracerebral hemorrhage (ICH; 614519), Weng et al. (2012) identified a heterozygous 1612C-G transversion in exon 25 of the COL4A1 gene, resulting in an arg538-to-gly (R538G) substitution at a residue conserved in mammals. This residue occurs within a repeat interruption and shortens the interruption from 7 to 4 amino acids, which could lead to abnormal alignment of peptides and interfere with proper heterotrimer assembly. The mutation was not found in 282 control chromosomes. In vitro functional expression studies showed that the mutant protein was retained intracellularly and was not secreted normally. The patient was a 55-year-old man with a history of hypertension and was taking low-dose aspirin.
In an 18-year-old Japanese man with brain small vessel disease-1 (BSVD1; 175780), Yoneda et al. (2013) identified a de novo heterozygous c.3976G-A transition in the COL4A1 gene, resulting in a gly1326-to-arg (G1326R) substitution at a highly conserved residue in the gly-X-Y repeat of the collagen triple-helical domain. Functional studies of the variant were not performed, but Yoneda et al. (2013) noted that impairment of the collagen IV heterotrimer assembly caused by mutant COL4A1 is a common pathologic mechanism. The mutation was not found in 200 Japanese controls. The patient had intellectual disability, spastic quadriplegia, and seizures. Brain imaging also showed schizencephaly, calcifications, and hemosiderin deposition. The report expanded the phenotype caused by mutations in the COL4A1 gene, and suggested that porencephaly and schizencephaly may result from a common pathologic mechanism.
In a Belgian man, his daughter, and his mother with brain small vessel disease-1 (BSVD1; 175780), Lemmens et al. (2013) identified a heterozygous 1-bp deletion (c.2085delC) in the COL4A1 gene, resulting in a frameshift and premature termination (Gly696fs). The mutation was not found in the 1000 Genomes Project, dbSNP (build 135), and Exome Variant Server databases, or in 744 control individuals. Patient cells showed no mutant COL4A1 mRNA, suggesting nonsense-mediated mRNA decay. Western blot analysis of patient cells showed a 41% reduction in COL4A1 expression; these findings were consistent with haploinsufficiency.
In affected members of a Dutch family (family B) with brain small vessel disease-1 (BSVD1; 175780), Lemmens et al. (2013) identified a heterozygous G-to-A transition in intron 29 of the COL4A1 gene (c.2194-1G-A), resulting in the skipping of exon 30 and premature termination. The mutation was not found in the 1000 Genomes Project, dbSNP (build 135), or Exome Variant Server databases. Analysis of patient cells indicated that the mutation caused nonsense-mediated mRNA decay, and Western blot analysis of patient cells showed a 50% reduction in COL4A1. These findings were consistent with haploinsufficiency. However, in the article by Lemmens et al. (2013), the affection status of members of family B differs between the text and figure 1, calling into question the cosegregation of the mutation with the phenotype in this family. Lemmens (2014) stated that 'Some of the patients were only clinically or genetically assessed which made statements about affection status difficult at the time.'
In a mother and daughter with brain small vessel disease-1 associated with hemorrhage, periventricular leukoencephalopathy, and ocular anomalies (BSVD1; 175780), Coupry et al. (2010) identified a c.2263G-A transition in exon 30 of the COL4A1 gene, resulting in a gly755-to-arg (G755R) substitution.
In a 14-year-old boy who developed transient left arm and leg weakness while jumping on a trampoline and was found to have acute intracranial hemorrhage as well as periventricular white matter changes, Shah et al. (2012) identified heterozygosity for the G755R substitution in the COL4A1 gene, which was not seen in 1,094 controls from the 1000 Genomes Project. The patient was found to be XYY on chromosome analysis and to be a carrier of the MTHFR 677C-T polymorphism (607093.0003). He had mild learning difficulties and also exhibited ocular features, including congenital cataract, hypermetropia, and astigmatism. There was no family history of migraine, stroke, or cataract. His asymptomatic parents, who were evaluated by a neurologist, did not undergo imaging and declined genetic testing.
In 2 sibs with brain small vessel disease and ocular anomalies (BSVD1; 175780), Shah et al. (2012) identified heterozygosity for a c.2317G-C transversion in the COL4A1 gene, resulting in a gly773-to-arg (G773R) substitution that was not found in 1,094 controls from the 1000 Genomes Project. The proband was a microcephalic boy with reduced visual acuity due to congenital cataracts, who exhibited spastic quadriplegia in infancy and developed symptoms of a 'stroke' at 4 years of age, losing speech and muscle tone and requiring feeding support due to bulbar/pseudobulbar weakness. His affected sib had very mild cataracts and right-sided infantile hemiplegia. Both sibs had white matter changes on brain MRI; the proband also had asymmetric ventricles with irregular margins, whereas his sib had a porencephalic cyst. Their mother, who had bilateral congenital cataracts, did not undergo imaging or genetic testing.
In a Hispanic brother and sister with congenital cataracts, marked microcornea, and moderate microphthalmia, who also had mild intellectual disability, Deml et al. (2014) identified heterozygosity for the c.2317G-A transition in exon 30 of COL4A1, resulting in the G773R substitution at a conserved residue in the triple helical domain. The mutation was not detected in blood samples from their unaffected parents or in a maternal buccal sample, suggesting that 1 parent had gonadal mosaicism for the COL4A1 mutation; the variant was also not found in the dbSNP, 1000 Genomes Project, and Exome Variant Server databases. Brain MRI at age 6 years in the sister showed nonspecific changes compatible with a small vessel disease process, but magnetic resonance angiography was normal.
In 9 affected members of a 4-generation family with multiple ocular anomalies, brain hemorrhage, and extensive leukoencephalopathy (BSVD1; 175780), originally described by Odland (1981), Rodahl et al. (2013) identified heterozygosity for a c.4881C-G transversion in exon 51 of the COL4A1 gene, resulting in an asn1627-to-lys (N1627K) substitution. The mutation was not found in 6 family members who had minor ocular anomalies but no neurologic symptoms, or in 185 blood donor controls.
In a 5-year-old Indian girl with congenital cataract, bilateral microcornea and Peters anomaly, unilateral microphthalmia, and unilateral retinal detachment (BSVD1; 175780), Deml et al. (2014) identified heterozygosity for a c.2122G-A transition in the COL4A1 gene, resulting in a gly708-to-arg (G708R) substitution at a conserved residue in the triple helical domain. The mutation was not detected in her mother, and her father was unavailable for screening; the variant was also not found in the dbSNP, 1000 Genomes Project, and Exome Variant Server databases. She had no history of developmental delay, and the only nonocular clinical feature reported was clinodactyly; imaging studies were not performed.
In a boy with brain small vessel disease-1 (BSVD1; 175780), renovascular hypertension, and retinal arteriosclerosis, who died at age 11 years from repeated alveolar hemorrhage from a tracheostoma, Abe et al. (2017) identified heterozygosity for a c.3104G-T transversion (c.3104G-T, NM_001845.5) in the COL4A1 gene, resulting in a gly1035-to-val (G1035V) substitution.
In 6 affected members from a large French family (F1) with autosomal dominant pontine microangiopathy and leukoencephalopathy (PADMAL; 618564), Verdura et al. (2016) identified a heterozygous c.*35C-A transversion (c.*35C-A, chr13.110,802,675G-T, GRCh37) in the 3-prime UTR of the COL4A1 gene. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the 1000 Genomes Project, Exome Variant Server, or ExAC databases. Targeted sequencing of this region of the gene in 202 unrelated probands with a similar disorder identified the same heterozygous c.*35C-A mutation in another patient (family 5) with a similar phenotype. In vitro functional expression studies in HEK293 cells showed that the mutation interfered with miRNA29 (see 610782) binding and resulted in increased expression of COL4A1 compared to wildtype. Levels of COL4A1 mRNA were increased in patient fibroblasts compared to controls.
In the proband from a German family (family 2) with autosomal dominant pontine microangiopathy and leukoencephalopathy (PADMAL; 618564), originally reported by Hagel et al. (2004), Verdura et al. (2016) identified a heterozygous c.*31G-T transversion in the 3-prime UTR of the COL4A1 gene in the miR29 (see 610782)-binding site. Linkage analysis using the extended pedigree confirmed the results. The mutation, which was found by targeted Sanger sequencing, was not found in the 1000 Genomes Project, Exome Variant Server, or ExAC databases. In vitro functional expression studies in HEK293 cells showed that the mutation interfered with miRNA29 (see 610782) binding and resulted in increased expression of COL4A1 compared to wildtype. Levels of COL4A1 mRNA were increased in patient fibroblasts compared to controls.
In affected members of 3 unrelated families (F3, F4, and F6) with autosomal dominant pontine microangiopathy and leukoencephalopathy (PADMAL; 618564), Verdura et al. (2016) identified a heterozygous c.*32G-T transversion in the 3-prime UTR of the COL4A1 gene in the miR29 (see 610782)-binding site. Linkage analysis using the extended pedigree of F3 confirmed the results. The mutation, which was found by targeted Sanger sequencing, was not found in the 1000 Genomes Project, Exome Variant Server, or ExAC databases. In vitro functional expression studies in HEK293 cells showed that the mutation interfered with miRNA29 binding and resulted in increased expression of COL4A1 compared to wildtype. Levels of COL4A1 mRNA were increased in patient fibroblasts compared to controls.
In affected members of a large 5-generation Swedish family with autosomal dominant pontine microangiopathy and leukoencephalopathy (PADMAL; 618564) originally reported by Sourander and Walinder (1977), Siitonen et al. (2017) identified a heterozygous c.*32G-A transition in the 3-prime UTR of the COL4A1 gene in the miR29 (see 610782)-binding site. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in control population databases, including ExAC and gnomAD. In vitro functional expression studies in HEK293 cells showed that the mutation interfered with miRNA29 (see 610782) binding and resulted in increased expression of COL4A1 compared to wildtype.
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