| *120240 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COLLAGEN, TYPE VI, ALPHA-2; COL6A2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HGNC Approved Gene Symbol: COL6A2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cytogenetic location: 21q22.3 Genomic coordinates (GRCh37): 21:47,518,032 - 47,552,762 (from NCBI) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Gene Phenotype Relationships | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Description | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| The COL6A2 gene encodes the alpha-2 subunit of type VI collagen, an ubiquitously expressed extracellular matrix protein. It is 1 of the 3 subunits comprising the full collagen VI protein (see also COL6A1; 120220 and COL6A3; 120250) (summary by Zhang et al., 2010). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cloning | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Weil et al. (1988) isolated clones corresponding to the COL6A2 gene from a human placenta expression library. Northern blot analysis detected a 3.5-kb mRNA transcript. The molecular mass of the protein is approximately 140 kD. Chu et al. (1989) determined that the COL6A2 protein contains 998 amino acids with 31% identity to COL6A1 in the N-terminal and C-terminal globular domains, which are connected by a triple helical segment. Both COL6A1 and COL6A2 contain small signal peptide sequences. Internal alignment of the globular sequences showed a repetitive 200-residue structure (15 to 23% identity) occurring 3 times (N1, C1, C2) in each chain. Sequencing of COL6A2 cDNA clones revealed 2 variant chains with a distinct C2 subdomain and 3-prime noncoding region. The repetitive segments C1, C2 and, to a lesser extent, N1 showed significant identity (15 to 18%) to the collagen-binding A domains of von Willebrand factor (VWF; 613160). These results suggested that the globular domains of the COL6 proteins bind to collagenous structures. Saitta et al. (1992) found that the human COL6A2 gene uses alternative processing to produce multiple mRNA transcripts differing in the 5-prime untranslated region as well as in the 3-prime coding and noncoding sequences. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Gene Structure | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Saitta et al. (1992) demonstrated that the COL6A2 gene contains 30 exons and spans 36 kb. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mapping | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| By somatic cell hybrid and FISH analysis, Weil et al. (1988) mapped the COL6A2 gene to chromosome 21q22.3. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Gene Function | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Klewer et al. (1998) studied COL6A2 gene expression in the developing mammalian heart. The pattern of expression was identical to that of COL6A1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 9 kindreds with the Bethlem form of autosomal dominant myopathy with contractures (158810), Jobsis et al. (1996) demonstrated genetic linkage to the COL6A1-COL6A2 cluster on 21q22.3. By sequence analysis in 4 families, Jobsis et al. (1996) identified a mutation in COL6A1 in 1 kindred and a mutation in COL6A2 in 2 others. Both mutations disrupted the Gly-X-Y motif of the triple helical domain by substitution of gly for either val or ser. Analogous to the putative perturbation of the anchoring function of the dystrophin-associated complex in congenital muscular dystrophy with mutations in the alpha-2-subunit of laminin (156225), the observation suggested a similar mechanism in Bethlem myopathy. Ullrich scleroatonic muscular dystrophy, also known as Ullrich congenital muscular dystrophy (UCMD; 254090), shares some clinical features with Bethlem myopathy, such as joint contractures, but displays a more severe course. Vanegas et al. (2001) demonstrated recessive mutations in the COL6A2 gene (see 120240.0002) leading to UCMD. Lampe et al. (2005) developed a method for rapid direct sequence analysis of all 107 coding exons of the COL6 genes (COL6A1, COL6A2, COL6A3; 120250) using single condition amplification/internal primer (SCAIP) sequencing. They sequenced all 3 COL6 genes from genomic DNA in 79 patients with UCMD or Bethlem myopathy, and found putative mutations in 1 of the COL6 genes in 62% of patients. Some patients showed changes in more than one of the COL6 genes, and some UCMD patients appeared to have dominant rather than recessive disease. Lampe et al. (2005) concluded that these findings may explain some or all of the cases of UCMD that are unlinked to the COL6 gene under a recessive model. In 2 unrelated patients with Bethlem myopathy, Baker et al. (2007) identified 2 different heterozygous mutations in the COL6A2 gene (120240.0009; 120240.0010). In vitro studies indicated defective collagen VI synthesis and secretion. In 2 sibs with autosomal recessive myosclerosis (255600), Merlini et al. (2008) identified a homozygous truncating mutation in the COL6A2 gene (120240.0011). Nadeau et al. (2009) identified a homozygous COL6A2 mutation (C777R; 120240.0012) in 3 patients with autosomal recessive UCMD. Two additional patients had 2 different heterozygous COL6A2 mutations (see, e.g., G283R, 120240.0013), consistent with autosomal dominant inheritance. Another patient was compound heterozygous for a mutation in the COL6A1 gene (G281R; 120220.0014) and a mutation in the COL6A2 gene (R498H; 120240.0014), consistent with digenic inheritance. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genotype/Phenotype Correlations | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Gualandi et al. (2009) reported 2 unrelated patients with Bethlem myopathy who were each compound heterozygous for a truncating and a missense mutation in the COL6A2 gene (Q819X, 120240.0011 and R830Q/R843W, 120240.0017; R366X, 120240.0018 and D871N; 120240.0019, respectively). Both patients remained ambulatory as adults, and muscle biopsies and studies of fibroblasts showed variable degrees of aberrant collagen VI microfilament formation. Gualandi et al. (2009) noted that autosomal recessive inheritance had not been reported in Bethlem myopathy and suggested that collagen VI-related myopathies comprise a spectrum of conditions with variable severity. In addition, the findings did not support pure haploinsufficiency as a causative mechanism for Bethlem myopathy, and suggested that some previously reported patients may harbor a second missed mutation. The genotype findings in these patients had important implications for genetic counseling. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ALLELIC VARIANTS (Selected Examples): | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Table View | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0001 BETHLEM MYOPATHY | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COL6A2, GLY250SER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 2 kindreds with Bethlem myopathy (158810), Jobsis et al. (1996) demonstrated that affected members had a heterozygous missense mutation (898G-A) resulting in a G250S amino acid substitution in the triple helical region. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0002 ULLRICH CONGENITAL MUSCULAR DYSTROPHY, AUTOSOMAL RECESSIVE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COL6A2, 1-BP INS, 1151C | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In an Italian family, Vanegas et al. (2001) found that a son with Ullrich congenital muscular dystrophy (254090) had a homozygous insertion of a C leading to a premature termination codon in the triple helical domain of COL6A2 mRNA. Both healthy consanguineous parents were carriers. The insertion of the C was in a stretch of 5 cytosines between nucleotides 1147 and 1151 of the COL6A2 cDNA, causing a slippage of the reading frame with a premature termination codon at nucleotides 1347-1349. The affected patient in this family showed reduced fetal movements. At birth he was unusually long (55 cm), showed multiple joint contractures of his knees and elbows, a kyphotic contracture of the spine, a left hip dislocation, bilateral congenital convex pes valgus, long and slender fingers and toes with adducted thumbs, ogival palatus, micrognathia, and a short neck with torticollis. He also showed marked bilateral distal hyperlaxity of fingers, toes, calcanei, and wrists. The child walked at the age of 13 months, but generalized muscle weakness persisted thereafter, and progressive scoliosis and respiratory failure developed. He underwent tracheostomy and nocturnal positive pressure mechanical ventilation at the age of 8 years, with signs of diaphragmatic insufficiency. At the age of 11 years, he was still ambulant and had normal intelligence. In fibroblasts from the patient reported by Vanegas et al. (2001), Zhang et al. (2002) showed almost complete absence of COL6A2 mRNA by Northern blot analysis, suggesting that the mutation led to nonsense-mediated mRNA decay. There was complete absence of secreted COL6A2 protein in the medium of the patient's cells, suggesting that the mutation in the triple helical domain prevented microfibrillar assembly and secretion. Although both parents showed decreased levels of COL6A2 mRNA, long-term collagen VI deposition was essentially normal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0003 ULLRICH CONGENITAL MUSCULAR DYSTROPHY, AUTOSOMAL RECESSIVE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COL6A2, IVS17, A-G, -2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In an Italian family, Vanegas et al. (2001) found that 2 brothers with Ullrich scleroatonic muscular dystrophy (254090) had a splice acceptor site mutation in the COL6A2 gene. Deletion of 28 nucleotides was caused by an A-to-G substitution at nucleotide -2 of intron 17, causing activation of a cryptic acceptor site within exon 18. The normal parents were unrelated. Severe contractures of elbows and knees, rigidity of the spine, ogival (gothic) palate, and hypotonia were present. In 1 brother there was distal hyperlaxity and marked weakness of head flexors but almost complete disappearance of limb joint contractures at the age of 2 years. In the brothers, this mutation was found in compound heterozygosity with a splice site mutation in intron 23 (120240.0004). The first mutation was present in the healthy mother, whereas the second mutation was carried by the healthy father. In another Italian family, Vanegas et al. (2001) found the same 28-bp deletion but did not find the mutation in the other allele. This mutation occurred de novo in the patient. In fibroblasts from 1 of the patients reported by Vanegas et al. (2001) who was a compound heterozygote for mutations in the COL6A2 gene, Zhang et al. (2002) showed decreased levels of COL6A2 mRNA by Northern blot analysis, suggesting that the mutations led to nonsense-mediated mRNA decay. Low levels of COL6A2 protein were detected in the medium of the patient's cells, suggesting that the mutations, which occurred at the distal part of the triple helical domain, allowed secretion of a small amount of mutant collagen VI protein. Further analysis showed that the truncated proteins were able to form triple helical monomers, but unable to assemble into dimers and tetramers for the completed collagen VI protein. Zhang et al. (2002) noted that the IVS23 mutation (120240.0004) retains the triple helical domain and thus can assemble into monomers, but has a shorter C-terminal globular domain which prevents further assembly into higher ordered structures. Although both parents showed decreased levels of COL6A2 mRNA, long-term collagen VI deposition was essentially normal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0004 ULLRICH CONGENITAL MUSCULAR DYSTROPHY, AUTOSOMAL RECESSIVE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COL6A2, IVS23, G-A, -1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Vanegas et al. (2001) described 2 brothers with Ullrich scleroatonic muscular dystrophy (254090) who were compound heterozygotes for 2 splice site mutations in the COL6A2 gene, one in intron 17 (120240.0003) and the other a G-to-A substitution at nucleotide -1 in intron 23. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0005 BETHLEM MYOPATHY | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COL6A2, ASP620ASN | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a Caucasian family from Mississippi and North Carolina, Scacheri et al. (2002) found 9 members with an autosomal dominant limb-girdle muscular dystrophy phenotype. A causative missense mutation, asp620 to asn (D620N), was present in heterozygous state. This mutation did not overtly affect the expression of proteins of the extracellular matrix (ECM), but did alter the expression of laminin beta-1 (150240) in the basement membrane of muscle fibers. Type VI collagen was thought to anchor the basal lamina to the extracellular matrix by interacting with collagen type IV, which in turn was thought to bind laminin beta-1 (Kuo et al., 1997). Scacheri et al. (2002) suggested that their studies widen the clinical spectrum of Bethlem myopathy (158810) and indicated that autosomal dominant limb-girdle muscular dystrophy should be studied for possible collagen VI etiology. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0006 ULLRICH CONGENITAL MUSCULAR DYSTROPHY, AUTOSOMAL RECESSIVE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COL6A2, 26-BP DEL, NT731 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a patient with Ullrich disease (254090), Higuchi et al. (2001) identified a homozygous 26-bp deletion (nucleotides 731-756) in exon 14 of the COL6A2 gene, causing a frameshift and premature termination codon, and resulting in a truncated collagen VI alpha-2 chain. Collagen VI expression was absent from the patient's skeletal muscle and skin samples. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0007 ULLRICH CONGENITAL MUSCULAR DYSTROPHY, AUTOSOMAL RECESSIVE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COL6A2, IVS12AS, A-G, -10 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a patient with Ullrich congenital muscular dystrophy (254090), Lucarini et al. (2005) identified a homozygous A-to-G transition in intron 12 of the COL6A2 gene, resulting in deletion of exon 13, which removed 21 amino acids from the N terminus of the triple helical domain. The misaligned N-terminal region was predicted to interfere with the assembly of collagen VI microfibrils. The intron mutation activated numerous cryptic acceptor sites, generating both normal and exon 13-deleted COL6A2 mRNA as well as multiple transcripts containing frameshifts that were degraded through nonsense-mediated decay. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0008 ULLRICH CONGENITAL MUSCULAR DYSTROPHY, AUTOSOMAL DOMINANT | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COL6A2, 1.3-KB DEL | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a patient with Ullrich congenital muscular dystrophy (254090), Baker et al. (2005) identified heterozygosity for a 1,332-bp deletion of the COL6A2 gene, which included part of intron 5, all of exon 6 and intron 6, and part of exon 7 and was predicted to result in loss of 27 amino acids in the triple helical region. The patient's mother was a mosaic carrier of the deletion. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0009 BETHLEM MYOPATHY | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COL6A2, IVS10AS, A-G, -2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a 40-year-old man with Bethlem myopathy (158810), Baker et al. (2007) identified a heterozygous A-to-G transition in intron 10 of the COL6A2 gene, resulting in the skipping of exon 11. Exon 11 codes for the only cysteine residue in the triple helical domain of the protein, which is predicted to form a disulfide bond critical for dimerization. This would result in decreased assembly of the collagen VI protein. Further evidence indicated nonsense-mediated decay of an mRNA with a premature stop codon, and reduced secretion of structurally abnormal collagen. The patient had proximal muscle weakness, decreased motor capacity, joint contractures, and dystrophic features on muscle biopsy. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0010 BETHLEM MYOPATHY | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COL6A2, PRO932LEU | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a 42-year-old Australian man with Bethlem myopathy (158810), Baker et al. (2007) identified a heterozygous 2795C-T transition in exon 28 of the COL6A2 gene, resulting in a pro932-to-leu (P932L) substitution in the globular C2 A-domain. Three first cousins and a niece were affected and also carried the mutation. The proband had proximal muscle weakness and joint contractures. Further studies indicated that the mutant P932L resulted in reduced intracellular collagen VI assembly and secretion. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0011 MYOSCLEROSIS, AUTOSOMAL RECESSIVE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BETHLEM MYOPATHY, AUTOSOMAL RECESSIVE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COL6A2, GLN819TER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 2 sibs, born of consanguineous parents, with autosomal recessive myosclerosis (255600), Merlini et al. (2008) identified a homozygous 2537C-T transition in exon 27 in the COL6A2 gene, resulting in a gln819-to-ter (Q819X) substitution in the C1 domain. RT-PCR studies showed that the mutation did not result in nonsense-mediated mRNA decay; the translated truncated protein lacked the C2 domain. Studies in patient fibroblasts showed decreased COL6A2 transcripts and decreased amounts of collagen VI deposited in the extracellular matrix. The secreted collagen VI microfibrils were abnormally organized and did not assemble properly into tetramers. The heterozygous parents were unaffected, suggesting that the mutation is not pathogenic in the heterozygous state. Gualandi et al. (2009) identified compound heterozygosity for the Q819X mutation and a complex missense allele (R830Q/R843W; 120240.0017) in a 25-year-old woman with Bethlem myopathy (158800). Although this genotype suggested autosomal recessive inheritance, the R819X mutation escaped nonsense-mediated decay and was thought not to be pathogenic in the heterozygous state, based on the report of Merlini et al. (2008). However, the fact that the woman reported by Gualandi et al. (2009) carried COL6A2 mutations on both alleles had implications for genetic counseling. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0012 ULLRICH CONGENITAL MUSCULAR DYSTROPHY, AUTOSOMAL RECESSIVE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COL6A2, CYS777ARG | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 3 patients with UCMD (254090), including 2 cousins, Nadeau et al. (2009) identified a homozygous 2329T-C transition in exon 26 of the COL6A2 gene, resulting in a cys777-to-arg (C777R) substitution. Onset ranged from birth to 2 years. One child had congenital hip dislocation. All had proximal muscle weakness and learned to walk independently at about 1 year of age, but became wheelchair-bound at ages 6.8, 9, and 11.5 years, respectively. Other features included spinal rigidity, scoliosis, and kyphosis. All also required nocturnal ventilation, and 1 needed gastrostomy for chewing difficulties. Only 1 had follicular hyperkeratosis. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0013 ULLRICH CONGENITAL MUSCULAR DYSTROPHY, AUTOSOMAL DOMINANT | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COL6A2, GLY283ARG | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a 20-year-old patient with UCMD (254090), Nadeau et al. (2009) identified a heterozygous 847G-A transition in exon 6 of the COL6A2 gene, resulting in a gly283-to-arg (G283R) substitution. The patient had onset at birth with hypotonia, contractures, scoliosis, and delayed motor development. Walking with support was achieved at age 3.3 years, but the patient became wheelchair-bound at age 10. Nocturnal ventilation was also required. Skin changes included follicular hyperkeratosis and keloid formation. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0014 ULLRICH CONGENITAL MUSCULAR DYSTROPHY, DIGENIC, COL6A1/COL6A2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COL6A2, ARG498HIS | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a 25-year-old patient with UCMD (254090), Nadeau et al. (2009) identified compound heterozygosity for 2 mutations in 2 different genes: a 1493G-A transition in exon 18 of the COL6A2 gene, resulting in an arg498-to-his (R498H) substitution, and a substitution in the COL6A1 gene (G281R; 120220.0014). The findings were consistent with digenic inheritance. The patient had onset at age 1.5 years of delayed motor development with proximal muscle weakness. Independent walking was achieved, but the patient became wheelchair-bound at age 19. Spinal rigidity, scoliosis, and contractures were also present, as well as follicular hyperkeratosis and a requirement for nocturnal ventilation. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0015 ULLRICH CONGENITAL MUSCULAR DYSTROPHY, AUTOSOMAL RECESSIVE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COL6A2, GLU624LYS | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a Brazilian girl with Ullrich congenital muscular dystrophy (265090), Zhang et al. (2010) identified a homozygous 1870G-A transition in the COL6A2 gene, resulting in a glu624-to-lys (E624K) substitution in the C1 globular subdomain. Sequence alignment and molecular modeling indicated that the mutation occurred in a consensus metal ion-dependent adhesion site (MIDAS). Patient fibroblasts deposited abundant collagen VI microfibrils that were thick and abnormally knotty. HEK293 cells transfected with the mutation assembled low levels of short collagen VI microfibrils. The E624K mutation did not affect collagen VI formation and assembly and did not exert a dominant-negative effect, as heterozygous family members were unaffected. However, the E624K-mutant chain was less efficient in supporting microfibrillar assembly than wildtype. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0016 ULLRICH CONGENITAL MUSCULAR DYSTROPHY, AUTOSOMAL RECESSIVE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COL6A2, ARG876SER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a young man, born of consanguineous Filipino parents, with Ullrich congenital muscular dystrophy (265090), Zhang et al. (2010) identified a homozygous 2626C-A transversion in the COL6A2 gene, resulting in an arg876-to-ser (R876S) substitution in the beta-2 strand of the C2 globular subdomain. Patient fibroblasts produced almost no collagen VI microfibrils in the extracellular matrix. The minute amounts of COL6A2 that were produced consisted of the C2a splice variant with a shorter alternative C2 subdomain not affected by the missense mutation. The C2a splice variant COL6A2 was not assembled into a triple-helical collagen VI molecule. HEK293 cells transfected with the R876S mutation showed intracellular retention of the mutant chain and were unable to synthesize normal collagen VI microfibrils. However, the patient showed a slightly less severe phenotype than another affected patient with a different mutation (see 120240.0015), suggesting that the low levels of COL6A2 with alternatively spliced C2a may have functionally compensated for loss of normal COL6A2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0017 BETHLEM MYOPATHY, AUTOSOMAL RECESSIVE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COL6A2, ARG830GLN AND ARG843TRP | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a 25-year-old woman with Bethlem myopathy (158810), Gualandi et al. (2009) identified compound heterozygosity for variations in the COL6A2 gene. The maternal allele carried a 2571G-A and a 2609C-T transition, both in exon 28, resulting in an arg830-t-gln (R830Q) and an arg843-to-trp (R843W) substitution, respectively, in the C2 domain. Both mutations affected highly conserved residues. The paternal allele carried a Q819X (120240.0011) substitution. The patient had onset of progressive proximal muscle weakness at age 2 years. During the course of the disorder, she developed prominent joint contractures and decreased forced vital capacity (65% of predicted), but retained independent ambulation. Muscle biopsy showed a myopathic pattern and fibrosis with mildly decreased collagen VI staining. Studies of fibroblasts showed absence of collagen VI tetramer formation, but electron microscopy showed correct filamentous and interconnected collagen VI microfilaments. Gualandi et al. (2009) concluded that this woman showed rare autosomal recessive inheritance of Bethlem myopathy based on her genotype. However, the authors noted that the R819X mutation escaped nonsense-mediated decay and was thought not to be pathogenic in the heterozygous state, based on the report of Merlini et al. (2008). The fact that the woman reported by Gualandi et al. (2009) carried COL6A2 mutations on both alleles had implications for genetic counseling. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0018 BETHLEM MYOPATHY, AUTOSOMAL RECESSIVE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COL6A2, ARG366TER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a 47-year-old man with Bethlem myopathy (158810), Gualandi et al. (2009) identified compound heterozygous mutations in the COL6A2 gene: a 1178C-T transition in exon 12, resulting in an arg366-to-ter (R366X) substitution, and a de novo 2693G-A transition in exon 28, resulting in an asp871-to-asn (D871N; 120240.0019) substitution in a conserved region of the C2 domain. The nonsense mutation was demonstrated to undergo nonsense-mediated decay. The patient's unaffected mother carried the heterozygous R377X mutation, suggesting that it is not pathogenic in the heterozygous state. The patient was born with talipes equinovarus and had Achilles contractures in childhood. He had limb-girdle weakness with joint contractures and reduced vital capacity (64% of predicted). At age 47, he could walk with aid, but could no longer rise from the floor. Muscle biopsy showed dystrophic features and decreased collagen VI. Studies of fibroblasts showed severely decreased levels of all forms of collagen VI, and electron microscopy showed irregular collagen VI microfilaments with absence of normal network structure. Gualandi et al. (2009) concluded that this patient had autosomal recessive Bethlem myopathy because of the genotype and his ability to remain ambulatory. The authors stated that the combination of a missense and a nonsense mutation in the COL6A2 gene had not previously been reported, yielding implications for genetic counseling. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0019 BETHLEM MYOPATHY, AUTOSOMAL RECESSIVE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COL6A2, ASP871ASN | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| See 120240.0018 and Gualandi et al. (2009). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| REFERENCES | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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