Alternative titles; symbols
HGNC Approved Gene Symbol: COL7A1
SNOMEDCT: 2689001, 48528004, 67653003, 723553000, 75875004;
Cytogenetic location: 3p21.31 Genomic coordinates (GRCh38): 3:48,564,073-48,595,329 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p21.31 | Epidermolysis bullosa dystrophica inversa | 226600 | Autosomal recessive | 3 |
| Epidermolysis bullosa dystrophica, autosomal dominant | 131750 | Autosomal dominant | 3 | |
| Epidermolysis bullosa dystrophica, autosomal recessive | 226600 | Autosomal recessive | 3 | |
| Epidermolysis bullosa dystrophica, Bart type | 132000 | Autosomal dominant | 3 | |
| Epidermolysis bullosa dystrophica, localisata variant | 226600 | Autosomal recessive | 3 | |
| Epidermolysis bullosa pruriginosa | 604129 | Autosomal dominant; Autosomal recessive | 3 | |
| Epidermolysis bullosa, pretibial | 131850 | Autosomal dominant; Autosomal recessive | 3 | |
| Nail disorder, nonsyndromic congenital, 8 | 607523 | Autosomal dominant | 3 | |
| Transient bullous of the newborn | 131705 | Autosomal dominant; Autosomal recessive | 3 |
The COL7A1 gene encodes the alpha-1 chain of type VII collagen. Collagen VII is the main constituent of anchoring fibrils, which in the skin are located below the basal lamina at the dermal-epidermal basement membrane zone. The collagen VII molecules form disulfide bond stabilized dimeric aggregates by lateral accretion in a nonstaggered array (Burgeson et al., 1985).
Bentz et al. (1983) isolated the collagen VII protein from human chorioamniotic membranes and found that the amino acid composition represented a distinct type of collagen composed of 3 identical alpha chains, each with a molecular mass of about 170 kD. The authors gave this collagen the trivial name 'long-chain' (LC) collagen and suggested that it be referred to as type VII collagen. Collagen VII has a triple-helical domain almost half again longer than the type I collagen triple helix.
Tanaka et al. (1992) isolated a cDNA clone corresponding to the COL7A1 gene from a human keratinocyte cDNA library. The deduced primary structure of the clone reflected the noncollagenous domain of type VII collagen that may be involved in cell attachment. This region showed weak homology (approximately 23%) to the cell attachment domain of fibronectin (FN1; 135600). Northern blot analysis detected a 9.5-kb mRNA transcript.
Christiano et al. (1994) isolated overlapping cDNA clones corresponding to the full-length human COL7A1 gene. The deduced 2,944-residue protein contains a central collagenous domain flanked by a large NH2-terminal noncollagenous (NC1) domain, which consists of submodules with homology to known adhesive proteins, including 9 fibronectin type III-like segments, and a smaller COOH-terminal noncollagenous (NC2) domain. The central collagenous domain is characterized by a repeating Gly-X-Y amino acid sequence. Northern blot analysis detected a 9.2-kb mRNA transcript.
Greenspan (1993) described the C-terminal half of type VII collagen and the intron/exon organization of the corresponding region of the COL7A1 gene.
Christiano et al. (1994) determined that the COL7A1 gene has 118 exons, more than any previously described gene. Despite this complexity, COL7A1 is compact with small introns. Consisting of 31,132 bp from transcription start site to polyadenylation site, it is only about 3 times the size of type VII collagen mRNA. A 71-nucleotide COL7A1 intron is the smallest intron reported in a collagen gene, and only 1 COL7A1 intron is greater than 1 kb long.
Knowlton et al. (1991) and Ryynanen et al. (1991) mapped the COL7A1 gene to chromosome 3 by analysis of human-rodent somatic cell hybrids.
By in situ hybridization, Parente et al. (1991) localized the COL7A1 gene to chromosome 3p21. By FISH, Greenspan et al. (1993) narrowed the assignment to 3p21.3.
By analysis of an interspecific backcross, Li et al. (1993) mapped the mouse Col7a1 gene to chromosome 9.
Type VII collagen appears to be restricted to the basement membrane zone beneath stratified squamous epithelia. Within the cutaneous basement membrane zone, type VII collagen localizes to the lamina densa and sublamina densa areas in the upper papillary dermis. More precisely, immunolocalization demonstrated that type VII collagen is a major collagenous component of anchoring fibrils (Ryynanen et al., 1992). Ryynanen et al. (1992) found a high level of COL7A1 expression in human epidermal keratinocytes and in an oral epidermoid carcinoma cell line with considerably lower expression in skin fibroblasts. Indirect immunofluorescence of skin from a 19-week human fetus showed type VII collagen gene expression at the dermal-epidermal basement membrane zone. The authors concluded that epidermal keratinocytes may be the primary cell source of type VII collagen in developing human skin.
Lapiere et al. (1993) identified 4 major immunodominant epitopes within the NC1 domain of COL7A1 using sera from 19 patients with acquired epidermolysis bullosa, EB acquisita (EBA), an autoimmune disorder resulting from autoantibodies to type VII collagen. The pattern of epitopes recognized by the sera from 3 patients with bullous systemic lupus erythematosus was similar to that found with EBA, suggesting that the same epitopes could serve as autoantigens in both blistering conditions. Sera from healthy controls or from patients with unrelated blistering skin diseases did not react with type VII collagen epitopes. Lapiere et al. (1993) postulated that such antibodies could disrupt the assembly of type VII collagen into anchoring fibrils and/or interfere with their interactions with other extracellular matrix molecules within the cutaneous basement membrane zone.
In mice, Ortiz-Urda et al. (2005) found that human epidermal cells devoid of collagen VII did not form tumors in mice, whereas those retaining the specific N-terminal NC1 domain were tumorigenic. Forced NC1 expression restored tumorigenicity to collagen VII-null epidermis in a non-cell-autonomous fashion. Fibronectin-like sequences within NC1 (FNC1) promoted tumor cell invasion in a laminin-5-dependent manner and were required for tumorigenesis. Ortiz-Urda et al. (2005) concluded that tumor-stroma interactions mediated by collagen VII promote neoplasia, and retention of NC1 sequences in a subset of patients with recessive dystrophic EB (RDEB; 226600) may contribute to their increased susceptibility to squamous cell carcinoma.
In 2 African American sibs with autosomal recessive dystrophic epidermolysis bullosa (226600), Christiano et al. (1993) identified a homozygous mutation in the COL7A1 gene (120120.0001). Heterozygous family members were clinically unaffected.
Christiano et al. (1995) identified nonsense mutations resulting in a premature protein termination in the N-terminal portion of the COL7A1 gene in 4 COL7A1 alleles from 3 unrelated patients with severe, mutilating recessive DEB. One of the patients was a compound heterozygote (120120.0005; 120120.0006). Heterozygous carriers of the nonsense mutations were clinically unaffected although they showed a 50% reduction in anchoring fibrils.
In descendants of the original family with Bart syndrome (132000), Christiano et al. (1996) identified a heterozygous mutation in the COL7A1 gene (120120.0008).
Christiano et al. (1996) reported 6 families with dystrophic epidermolysis bullosa. Two families with autosomal dominant inheritance (DDEB; 131750) showed a relatively mild phenotype, whereas 4 with autosomal recessive inheritance showed a severe phenotype. Genetic analysis identified glycine substitution COL7A1 mutations in affected members of all families. Those with dominant inheritance had heterozygous glycine substitution mutations. Two families with recessive inheritance were compound heterozygous for a glycine substitution and a premature termination mutation (see, e.g., 120120.0036; 120120.0037), whereas the other 2 families with recessive inheritance were homozygous for a glycine substitution (see, e.g., 120120.0038). In all 4 recessive families, the glycine substitution mutation was silent in heterozygous carriers who had no disease manifestation. Christiano et al. (1996) stated that the COL7A1 gene is thus unique among the collagen genes in that different glycine substitutions can be either silent in heterozygotes or can result in a dominantly inherited DEB. Inspection of the location of the glycine substitutions did not show a positional effect in terms of phenotype or pattern of inheritance.
In twins with severe recessive DEB, Christiano et al. (1996) identified compound heterozygosity for 2 mutations in the COL7A1 gene. The paternal allele carried a recessive deletion/insertion mutation and the maternal allele had a dominant-negative maternal glycine substitution. Careful questioning of the mother revealed that she and her father had a history of shedding of toenails and an occasional poor healing of erosions, consistent with a mild form of dominantly inherited DEB.
Based on PCR amplification of COL7A1 genomic sequences, Kon et al. (1998) conducted a mutation analysis in 9 families with dystrophic epidermolysis bullosa, including 7 with recessive inheritance and 2 with dominant inheritance. The results uncovered 16 different mutations, 11 of which were novel. The authors used the genetic information for prenatal testing in a family at risk for recurrence of a severe Hallopeau-Siemens type of recessive DEB.
Rouan et al. (1998) found glycine substitution COL7A1 mutations in all of 6 families in which the proband had clinical features and/or ultrastructural findings consistent with dystrophic epidermolysis bullosa. Four of the mutations were novel. De novo mutations were identified in 3 families. The results emphasized the predominance of glycine substitution mutations in dominant DEB and indicated that in some cases the phenotype is due to de novo mutations. In families of the latter type, the pedigree pattern alone might not permit distinction of dominant and recessive DEB.
In a patient with transient bullous dermolysis of the newborn (TBDN; 131705), Hammami-Hauasli et al. (1998) identified compound heterozygous mutations in the COL7A1 gene (G1519D; 120120.0015 and G2251E; 120120.0014). In the heterozygous state, G1519D was known to be silent, and G2251E led to isolated toenail dystrophy without skin blistering, here designated nonsyndromic congenital nail disorder-8 (NDNC8; 607523). In the proband, compound heterozygosity for the mutations caused massive, transitory retention of collagen VII in the epidermis, its reduced deposition at the basement membrane zone, and extensive dermoepidermal separation at birth. TBDN keratinocytes in vitro accumulated collagen VII intracellularly in the rough endoplasmic reticulum. Because of the self-limiting course of the disorder and its distinctive morphologic features, TBDN has been grouped separately from dystrophic epidermolysis bullosa.
In the family of a 10-year-old Japanese girl with moderately severe DEB, previously reported by Hatta et al. (1995), who was compound heterozygous for missense mutations in the COL7A1 gene, G2316R (120120.0042) and G2287R (120120.0023), Shimizu et al. (1999) found that all heterozygous carriers of the G2287R mutation, including the proband's mother, maternal uncle, and maternal grandmother, had mild nail dystrophy restricted to the great toenails without skin fragility (607523), whereas individuals carrying the paternally inherited G2316R mutation were clinically unaffected.
Mellerio et al. (1999) studied 6 unrelated patients with a distinct clinical subtype of dystrophic epidermolysis bullosa: epidermolysis bullosa pruriginosa (604129), which is characterized by pruritus, excoriated prurigo nodules, and skin fragility. Mutation analysis using PCR amplification of genomic DNA, heteroduplex analysis, and direct nucleotide sequencing demonstrated pathogenetic COL7A1 mutations in each case (see, e.g., 120120.0017-120120.0020). Four patients had a glycine substitution mutation on 1 COL7A1 allele, 1 patient was a compound heterozygote for a splice site mutation and a single basepair deletion, and 1 patient was heterozygous for an out-of-frame deletion mutation. Both autosomal dominant and autosomal recessive inheritance was shown.
Sato-Matsumura et al. (2002) studied 2 unrelated Japanese families with recessive dystrophic epidermolysis bullosa in which isolated toenail dystrophy also segregated as an autosomal dominant trait. In family members with dystrophic changes limited to the toenails but without skin fragility (607523), they identified heterozygosity for the glycine substitutions G1595R (120120.0024) and G1815R (120120.0025), respectively. The patients with RDEB in each family were compound heterozygous for 1 of these mutations, respectively, in combination with a nonsense (Q2827X; 120120.0043) or a frameshift mutation (5818delC; 120120.0006) in COL7A1. These results supported the idea that certain glycine substitutions in the collagenous domain of COL7A1 cause a limited nail deformity, and that these alleles can also contribute to variable degrees of skin fragility when present in combination with nonsense or frameshift mutations in COL7A1.
A missense mutation leading to the replacement of 1 gly in the (Gly-Xaa-Yaa)n repeat of the collagen triple helix can cause a range of heritable connective tissue disorders that depend on the gene in which the mutation occurs. Persikov et al. (2004) found that the spectrum of amino acids replacing Gly was not significantly different from that expected for the COL7A1-encoded collagen chains, suggesting that any Gly replacement can cause dystrophic epidermolysis bullosa. On the other hand, the distribution of residues replacing Gly was significantly different from that expected for all other collagen chains related to disease, with a particularly strong bias seen for the collagen chains encoded by COL1A1 (120150) and COL3A1 (120180), which are related to osteogenesis imperfecta (166200) and to Ehlers-Danlos syndrome type IV (130050), respectively. The bias did not correlate with the degree of chemical dissimilarity between Gly and the replacement residues, but in some cases a relationship was observed with the predicted extent of destabilization of the triple helix.
Varki et al. (2007) analyzed the COL7A1 gene in 310 patients with dystrophic epidermolysis bullosa. Mutations were found in 1 or both alleles in 243 (78.4%) patients, comprising 355 mutant alleles of the anticipated 438 (81.1%) mutant alleles. The authors reviewed the spectrum of COL7A1 mutation and genotype-phenotype correlations. Seven patients had features of both dominant and recessive forms of disease and were found to carry both dominant and recessive mutations.
Reviews
Jarvikallio et al. (1997) reviewed mutations in the COL7A1 gene as maintained in a database in Philadelphia.
Hovnanian et al. (1997) characterized 21 mutations in the COL7A1 gene, including 18 novel mutations, in patients from 15 unrelated families with recessive dystrophic epidermolysis bullosa. Mutations in both alleles were identified by screening the 118 exons of COL7A1 and flanking intronic regions. Fourteen mutations created premature termination codons and consisted of nonsense mutations, small insertions, deletions, and splice site mutations. A further 7 mutations predicted glycine or arginine substitutions in the collagenous domain of the molecule. Two mutations were found in more than 1 family, and 6 of the 7 missense mutations showed clustering within exons 72 to 74 next to the hinge region of the protein. Patients who were homozygous or compound heterozygous displayed both absence or drastic reduction of COL7A1 transcripts and undetectable type VII collagen in skin. In contrast, missense mutations were associated with clearly detectable COL7A1 transcripts and with normal or reduced expression of type VII collagen at the dermo/epidermal junction. The results provided evidence for at least 2 distinct molecular mechanisms underlying defective anchoring fibril formation in RDEB: one involving premature termination codons leading to mRNA instability and absence of protein synthesis, the other implicating missense mutations resulting in the synthesis of type VII collagen with decreased stability and/or altered function. Genotype/phenotype correlations suggested to Hovnanian et al. (1997) that the nature and location of these mutations are important determinants of the disease phenotype and show evidence for interfamilial phenotypic variability.
Hammami-Hauasli et al. (1998) investigated naturally occurring COL7A1 mutations and showed that some, but not all, glycine substitutions in collagen VII interfere with biosynthesis of the protein in a dominant-negative manner. Three point mutations in exon 73 caused glycine substitutions, G2006D, G2034R, and G2015E, in the triple helical domain of collagen VII and interfered with its folding and secretion. Confocal laser scanning studies and semiquantitative immunoblotting determined that dystrophic epidermolysis bullosa keratinocytes retained up to 2.5-fold more procollagen VII within the rough endoplasmic reticulum than controls. In contrast, the glycine substitution G1519D in another segment of the triple helix affected neither procollagen VII secretion nor anchoring fibril function and remained phenotypically silent. Thus, collagen VII is a remarkable exception among collagens in that not all glycine substitutions within the triple helix exert dominant-negative interference. The biologic consequences of the substitutions probably depend on their position within the triple helix.
Van den Akker et al. (2011) reviewed the 29 known full genotypes associated with RDEB inversa from their study and the literature and found that the functional genotype in the disorder is a homozygous, compound heterozygous, or hemizygous missense mutation within the triple helical domain of COL7A1. Of the 19 known missense mutations, all involved substitutions of arginine or glycine. Three of the 5 arginine substitutions (e.g., R2063G) and 9 of the 14 glycine substitutions (e.g., G1907E) were specific to the inversa form of RDEB.
In an inbred breed of golden retriever dogs with RDEB and aberrant expression of collagen type VII reported by Palazzi et al. (2000), Baldeschi et al. (2003) isolated and analyzed the 9-kb dog COL7A1 cDNA and identified a 5716G-A transition in exon 68, resulting in a gly1906-to-ser (G1906S) substitution at a conserved residue. Highly efficient transfer of the wildtype COL7A1 cDNA to both dog RDEB and human primary RDEB COL7A1-null keratinocytes, using recombinant retrovirus vectors, achieved sustained and permanent expression of the transgene product. The expression and posttranslational modification profile of the recombinant collagen type VII was comparable to that of the wildtype counterpart. The recombinant canine collagen type VII in human RDEB keratinocytes and dog cells corrected the observable defects caused by RDEB keratinocytes in cell cultures and in vitro reconstructed skin. Baldeschi et al. (2003) concluded that not only infection efficiency but also high expression levels may be required to ensure therapeutic efficacy in the presence of mutated gene products.
Fritsch et al. (2008) developed a transgenic mouse model with conditional inactivation of Col7a1 expression resulting in a Col7a1 hypomorphic animal expressing about 10% of normal Col7a1 levels. Homozygous mice appeared normal at birth, but developed blisters on the paws by 24 to 48 hours after birth. Hypomorphic mice showed poor general condition resulting from poor nutrition and blisters of the tongue. A liquid diet resulted in increased survival. Mitten deformities of the paws were found to result from soft tissue accumulation and contraction due to aberrant fibrosis that accompanied wound healing. The features resembled those of human recessive DEB, including skin fragility, nail dystrophy, pseudosyndactyly, and growth retardation. Intradermal injection with wildtype fibroblasts restored Col7a1 deposition and function and resulted in phenotypic improvement.
In an African American family in which 4 individuals related as first cousins once removed had autosomal recessive epidermolysis bullosa dystrophica (226600), Christiano et al. (1993) used single-strand conformation polymorphism (SSCP) electrophoresis and sequencing to demonstrate a T-to-A transversion in the COL7A1 gene, resulting in a met2798-to-lys (M2798K) substitution. The mutation was homozygous in 2 affected sibs, while their unaffected mother and half brother were heterozygous. The mutation resided in a highly conserved region of the C terminus of type VII collagen and was not found in 194 alleles from unrelated, unaffected African American individuals when screened with a restriction analysis based on a new restriction site for the endonuclease EarI created by the mutation.
In affected members of a large 5-generation Finnish family reported by Ryynanen et al. (1991) as having the Cockayne-Touraine type of autosomal dominant dystrophic epidermolysis bullosa (131750), Christiano et al. (1994) identified a heterozygous 6118G-A transition in exon 73 of the COL7A1 gene, resulting in a gly2040-to-ser (G2040S) substitution in the triple helical domain. Christiano et al. (1994) noted that some family members had the Pasini type of DDEB. The authors postulated that the phenotype resulted from a dominant-negative effect in type VII collagen, resulting in the formation of structurally abnormal anchoring fibrils.
In a 35-year-old Hispanic male with recessive epidermolysis bullosa dystrophica (226600), Christiano et al. (1994) found compound heterozygosity for 2 nonsense mutations in the COL7A1 gene: a 1-bp insertion (2470insG) in exon 19, and a 1-bp deletion (3858delG; 120120.0004) in exon 31. Both mutations resulted in truncated proteins. Clinical features included extreme fragility of the skin and the mucous membranes of the upper gastrointestinal tract, leading to extensive mutilating scarring and joint contractures. Heterozygous family members were unaffected.
For discussion of the 1-bp deletion in the COL7A1 gene (3858delG) that was found in compound heterozygous state in a patient with autosomal recessive epidermolysis bullosa dystrophica (226600) by Christiano et al. (1994), see 120120.0003.
In 3 Japanese brothers with severe, mutilating recessive dystrophic epidermolysis bullosa (226600), Christiano et al. (1995) found compound heterozygosity for 2 nonsense mutations in the COL7A1 gene: a C-to-A transversion resulting in a tyr311-to-ter (Y311X) substitution, and a 1-bp deletion (5818delC; 120120.0006).
For discussion of the 1-bp deletion in the COL7A1 gene (5818delC) that was found in compound heterozygous state in patients with autosomal recessive epidermolysis bullosa dystrophica (226600) by Christiano et al. (1995), see 120120.0005.
Also see 120120.0025 and Sato-Matsumura et al. (2002).
In affected members of a large 5-generation family of Taiwanese descent with pretibial epidermolysis bullosa (131850), Christiano et al. (1995) identified a 7687G-T transversion in exon 105 of the COL7A1 gene, resulting in a gly2623-to-cys (G2623C) substitution. The mutation was confirmed in affected family members using the loss of a SmaI restriction site, and when used for linkage analysis, together with an intragenic PvuII polymorphism in several flanking markers, resulted in a lod score of 3.61 at theta = 0.0 in this family. The findings confirmed that the pretibial variant of epidermolysis bullosa is allelic to autosomal dominant dystrophic EB (131750).
In affected individuals from the original family with Bart syndrome (132000) reported by Bart et al. (1966), Christiano et al. (1996) identified a heterozygous 6007G-A transition in exon 73 of the COL7A1 gene, resulting in a gly2003-to-arg (G2003R) substitution within the triple helical domain. The findings indicated that Bart syndrome is a clinical variant of dominant dystrophic epidermolysis bullosa (131750). Christiano et al. (1996) postulated that the clinical differences in the phenotype of the several forms of dominant dystrophic EB may result from the specific location of the glycine substitutions within exon 73.
In a patient with the localisata variant of recessive epidermolysis bullosa dystrophica (see 226600), a mild form of recessive DEB in which blistering and scarring are predominantly localized to the extremities, Gardella et al. (1996) identified 2 splicing mutations in the COL7A1 gene: a paternally inherited A-to-G transition at position -2 of the donor splice site of intron 3, and a maternally inherited G-to-A transition at position -1 of the donor splice site of intron 95 (120120.0010). Both mutations resulted in aberrant forms of mRNA. Allele-specific analysis of the transcripts indicated to Gardella et al. (1996) that the maternal mutation did not completely abolish correct splicing of COL7A1 pre-mRNA and that synthesis of a certain level of functional protein was observed. This result was compatible with the mild phenotype.
Drera et al. (2006) identified compound heterozygosity for the 2 splice site mutations reported by Gardella et al. (1996) in an Italian patient with epidermolysis bullosa pruriginosa (604129).
For discussion of the maternally inherited splice site mutation in the COL7A1 gene (IVS95-1G-A) that was found in compound heterozygous state in a patient with the localisata variant of recessive epidermolysis bullosa dystrophica (see 226600) by Gardella et al. (1996), see 120120.0009. This mutation resulted in aberrant forms of mRNA from COL7A1.
Drera et al. (2006) identified compound heterozygosity for the 2 splice site mutations reported by Gardella et al. (1996) in an Italian patient with epidermolysis bullosa pruriginosa (604129). Another patient with the pruriginosa phenotype was compound heterozygous for the IVS95DS splice site mutation and a nonsense mutation (R1630X; 120120.0032).
In a nonconsanguineous Italian family in which 3 sibs had an unusually mild form of localized recessive epidermolysis bullosa dystrophica (see 226600), Terracina et al. (1998) found compound heterozygosity for 2 mutations in the COL7A1 gene. The maternally inherited allele carried a G-to-C transversion, resulting in a gly1347-to-arg (G1347R) substitution, and the paternally inherited allele carried a G-to-A transition at the last base of exon 70 (5820G-A) that altered the splicing of COL7A1 pre-mRNA, giving rise to an aberrant mRNA carrying the in-frame skipping of exon 70 in addition to the full-length RNA transcript carrying the G-to-A substitution (120120.0012). The combination of a recessive glycine substitution with a splice site mutation that permitted partially correct splicing led to normal expression of mutated type VII collagen molecules with marginally altered biologic activity and to the extremely mild phenotype observed in these patients. The affected sibs were aged 30, 28, and 27 years. The parents and 2 other sibs were unaffected. All 3 patients had skin blisters and erosions from their first month of life. During early childhood, lesions were strictly localized to trauma-exposed sites, i.e., elbows, knees, hands, and feet, whereas from early adulthood onwards, they appeared exclusively on the palmar and dorsal surfaces of hands and, to a lesser extent, feet. The lesions resolved with mild scarring and milia formation. Dystrophy of fingernails and toenails was observed, whereas mucosae, hair, and teeth showed no lesions.
For discussion of the 5820G-A transition in exon 70 of the COL7A1 gene that was found in compound heterozygous state in patients with the localisata variant of recessive epidermolysis bullosa dystrophica (see 226600) by Terracina et al. (1998), see 120120.0011.
In a girl with the severe Hallopeau-Siemens type of recessive epidermolysis bullosa dystrophica (226600), Kon et al. (1998) identified a homozygous 4119+1G-T transversion involving the first nucleotide of intron 35 of the COL7A1 gene. Examination of the sequence of exon 35 indicated that if this mutation resulted in skipping of the entire exon 35, the deletion would be in-frame, resulting in elimination of 24 amino acids from the N-terminal globular domain of type VII collagen. Both unaffected parents were heterozygous for the 4119+1G-T mutation. The mutation created a new restriction enzyme site for MseI. Two fetuses to which prenatal diagnosis was applied were genotypically normal.
In a 14-month-old girl with transient bullous dermolysis of the newborn (TBDN; 131705), Hammami-Hauasli et al. (1998) identified compound heterozygosity for a 6752G-A transition in exon 86 of the COL7A1 gene, resulting in a gly2251-to-glu (G2251E) substitution, and a 4556G-A transition in exon 44, resulting in a gly1519-to-asp (G1519D; 120120.0015) substitution. The patient's mother, a heterozygous carrier of the G2251E mutation, had isolated toenail dystrophy without skin lesions (NDNC8; 607523), whereas the father, who carried the G1519D mutation, was clinically unaffected.
Ee et al. (2007) reported a Chinese-Singaporean family in which a heterozygous COL7A1 G2251E mutation segregated with autosomal dominant epidermolysis bullosa pruriginosa (604129). The disorder showed relatively late onset in teenage or young adult years.
For discussion of the gly1519-to-asp (G1519D) mutation in the COL7A1 gene that was found in compound heterozygous state in a patient with transient bullous dermolysis of the newborn (TBDN; 131705) by Hammami-Hauasli et al. (1998), see 120120.0014.
In a Hispanic-Mexican woman with the Pasini type of dominant epidermolysis bullosa dystrophica (131750), Mellerio et al. (1998) identified a heterozygous 6127G-A transition in exon 73 of the COL7A1 gene, resulting in a gly2043-to-arg (G2043R) substitution. The same mutation was found in 3 affected individuals from an unrelated Scottish family with dominant epidermolysis bullosa dystrophica. Although both families had some clinical features of the Pasini type, there was considerable interfamilial and intrafamilial variability. The mutation had previously been identified in 3 other families with dominant DEB, 1 Italian, 1 Hungarian, and 1 Norwegian.
In a 34-year-old Caucasian male with autosomal dominant epidermolysis bullosa pruriginosa (604129), Mellerio et al. (1999) identified a heterozygous gly2242-to-arg (G2242R) substitution in exon 85 of the COL7A1 gene. Clinical features included skin fragility, pruritus, nodular prurigo-like lesions, and nail dystrophy from the age of 7 years. His father also had mild blistering and excoriations consistent with autosomal dominant inheritance.
The G2242R mutation was found by Lee et al. (1997) in a Taiwanese pedigree with autosomal dominant EB pruriginosa.
In a 13-year-old Caucasian girl with epidermolysis bullosa pruriginosa (604129), Mellerio et al. (1999) found compound heterozygosity for 2 mutations in the COL7A1 gene: a splice site mutation (5532+1G-A) in intron 64, and a 1-basepair deletion in exon 104 (7786delG; 120120.0019). She had widespread linear prurigo lesions on her limbs, skin fragility, pruritus, and nail involvement all starting in infancy. There was no family history of skin disease.
For discussion of the 1-bp deletion in the COL7A1 gene (7786delG) that was found in compound heterozygous state in a patient with epidermolysis bullosa pruriginosa (604129) by Mellerio et al. (1999), see 120120.0018.
In affected members of a Hispanic Mexican family with a 5-generation history of epidermolysis bullosa pruriginosa (604129), Mellerio et al. (1999) identified a 16-bp deletion in exon 87 of the COL7A1 gene. The mutation was present in a 38-year-old man who had developed features of EB pruriginosa at age 11 years and also in his 10-year-old daughter with mild features of EB pruriginosa. The pedigree had been described by Cserhalmi-Friedman et al. (1998), who showed that the mutation resulted in in-frame skipping of exon 87, which consists of 69 bp, rather than a frameshift and downstream premature termination codon. This phenomenon had been described for other autosomal dominant deletion mutations in COL7A1 (Sakuntabhai et al., 1998).
Betts et al. (1999) described a 33-year-old Italian man with pretibial epidermolysis bullosa (131850) who was apparently a compound heterozygote for a splice site mutation inherited from his healthy father and transmitted to his healthy son. Mutation search in the COL7A1 gene revealed a 14-bp deletion in the 115 exon-intron boundary (33563del14), which resulted in the in-frame skipping of exon 115 with elimination of 29 amino acids from the pro-alpha-1(VII) polypeptide chain. As a consequence, procollagen VII failed to be processed to mature collagen VII and accumulated at the dermal-epidermal junction, as revealed by immunofluorescence staining using an NC-2 domain-specific antibody. The pathogenic mutation inherited from the mother remained to be identified. This was thought to be the first report of a recessive deletion mutation in pretibial epidermolysis bullosa.
Winberg et al. (1997) had identified the 14-bp deletion in compound heterozygosity with G2043R (120120.0016) in a Norwegian/Swedish woman with autosomal recessive dystrophic EB (226600).
Nordal et al. (2001) reported monozygous triplets equally affected with recessive dystrophic epidermolysis bullosa (226600). Mutation analysis in this family revealed a homozygous gly2031-to-ser (G2031S) substitution in exon 73 of the COL7A1 gene. Most glycine substitutions in this gene region encoding for the triple helical domain of collagen VII had been associated with milder, dominantly inherited phenotypes. By contrast, the novel point mutation of this study was clinically silent in the heterozygous state and resulted in a severe phenotype when homozygous.
In a 10-year-old Japanese girl with moderately severe epidermolysis bullosa dystrophica (226600), originally reported by Hatta et al. (1995), Shimizu et al. (1999) identified compound heterozygosity for a 6859G-A transition in exon 87 of the COL7A1 gene, resulting in a gly2287-to-arg (G2287R) substitution, and a 6946G-A transition in exon 89, resulting in a gly2316-to-arg (G2316R; 120120.0042) substitution. All heterozygous carriers of the G2287R mutation, including the proband's mother, maternal uncle, and maternal grandmother, had mild nail dystrophy restricted to the great toenails without skin fragility (NDNC8; 607523). Individuals heterozygous for the paternal G2316R mutation were clinically unaffected.
In a Japanese male patient with moderately severe epidermolysis bullosa dystrophica (226600), Sato-Matsumura et al. (2002) identified compound heterozygosity for a 4783G-C transversion in the COL7A1 gene, resulting in a gly1595-to-arg (G1595R) substitution, and an 8479C-T transition, resulting in a gln2827-to-ter (Q2827X; 120120.0043) substitution. The patient's father and his paternal grandmother, who were heterozygous for the G1595R mutation, displayed isolated toenail dystrophy (NDNC8; 607523) without skin fragility.
In a Japanese female patient with moderately severe epidermolysis bullosa dystrophica (226600), Sato-Matsumura et al. (2002) identified compound heterozygosity for a 5443G-A transition in the COL7A1 gene, resulting in a gly1815-to-arg (G1815R) substitution, and the previously reported 5818delC frameshift mutation (120120.0006). In this family, isolated toenail dystrophy (NDNC8; 607523) was also present in 7 family members, segregating in an autosomal dominant fashion over 4 generations; those affected were found to be heterozygous for the G1815R mutation.
In a father and son with the Pasini type of dominant dystrophic epidermolysis bullosa (131750) reported by Konig et al. (1994), Hammami-Hauasli et al. (1998) identified a heterozygous 6017G-A transition in exon 73 of the COL7A1 gene, resulting in a gly2006-to-asp (G2006D) amino acid substitution.
In affected members of a large family with dominant dystrophic epidermolysis bullosa (131750), Hammami-Hauasli et al. (1998) found a 6044G-A transition in exon 73 of the COL7A1 gene, resulting in a gly2015-to-glu (G2015E) substitution. Specific details of the phenotype were not provided.
In affected members of a large family with autosomal dominant epidermolysis bullosa dystrophica of the Cockayne-Touraine type (131750), Kon et al. (1997) identified a heterozygous 6100G-A transition in exon 73 of the COL7A1 gene, resulting in a gly2034-to-arg (G2034R) substitution. Hammami-Hauasli et al. (1998) and Mecklenbeck et al. (1999) also found the G2034R mutation in 2 additional families with DDEB, although specific phenotypic subtypes were not reported.
Martinez-Mir et al. (2002) identified heterozygosity for the G2034R substitution in affected members of a family with an unusual epidermolysis bullosa phenotype. The family was first reported by Fine et al. (1989) as epidermolysis bullosa simplex superficialis (607600) because skin biopsies showed clefts of variable size just below the stratum corneum or intraepidermal without changes in the sublamina densa. However, the clinical features also included those reminiscent of dominant dystrophic EB, including scarring, milia, nail dystrophy, and blistering involving the oral cavity. Based on the molecular findings, Martinez-Mir et al. (2002) reclassified the phenotype in this family as a clinical variant of dominant dystrophic epidermolysis bullosa.
In a patient with autosomal recessive pretibial epidermolysis bullosa (131850), Gardella et al. (2002) identified compound heterozygous mutations in the COL7A1 gene: a 5096C-T transition in exon 55 resulting in a pro1699-to-leu (P1699L) substitution, and a splice site mutation in intron 2 (120120.0030).
In a patient with autosomal recessive pretibial epidermolysis bullosa (131850), Gardella et al. (2002) reported a splicing mutation in the COL7A1 gene, 267-1G-C, which abolished the conserved acceptor splice site of intron 2. This mutation occurred in compound heterozygosity with a missense mutation (120120.0029).
In a Japanese father and daughter with autosomal dominant dystrophic epidermolysis bullosa (131750), Sawamura et al. (2006) identified a heterozygous 6110G-A transition in the COL7A1 gene, resulting in a gly2037-to-glu (G2037E) substitution. Functional transfection expression studies showed that the mutant G2037E protein resulted in intracellular accumulation of collagen VII within human epidermal keratinocytes in a dominant-negative manner. Albopapuloid lesions were not noted.
In an Italian patient with autosomal recessive epidermolysis bullosa pruriginosa (604129), Drera et al. (2006) identified compound heterozygosity for 2 mutations in the COL7A1 gene: an arg1630-to-ter (R1630X) substitution in exon 51 and a splice site mutation in exon 95 (120120.0010).
In an Italian father and daughter with autosomal dominant epidermolysis bullosa pruriginosa (604129), Drera et al. (2006) identified a heterozygous 6218G-T transversion in exon 75 of the COL7A1 gene, resulting in a gly2073-to-val (G2073V) substitution in the collagenous domain.
In 3 brothers, born of consanguineous parents, with epidermolysis bullosa dystrophica (226600), Hovnanian et al. (1997) identified a homozygous 6187C-T transition in exon 74 of the COL7A1 gene, resulting in an arg2063-to-trp (R2063W) substitution. The boys showed marked phenotypic variability, with the eldest being most severely affected, the middle brother having intermediate severity, and the youngest having a milder, localized form of the disorder.
In the family reported by Hovnanian et al. (1997), Titeux et al. (2008) found that disease severity was not correlated with residual COL7A1 mRNA or protein levels, but was correlated with residual protein at the dermal-epidermal junction, suggesting increased degradation. The 2 most severely affected boys had increased mRNA and protein levels of interstitial collagenase (MMP1; 120353), and they were found to carry a SNP in the MMP1 gene (120353.0001) that resulted in increased transcription of MMP1, greater COL7A1 degradation, and thus more severe disease manifestations.
In a 42-year-old Japanese woman with the Pasini form of dominant dystrophic epidermolysis bullosa (131750), Kon et al. (1997) identified a heterozygous 6227G-A transition in the COL7A1 gene, resulting in a gly2076-to-asp (G2076D) substitution in the triple helical domain. She had blistering since infancy and developed multiple white papules on her back at age 17 years. Her 2-year-old son, who also carried the mutation, was similarly affected.
In a 3-year-old boy with autosomal recessive epidermolysis bullosa dystrophica (226600), Christiano et al. (1996) identified compound heterozygosity for 2 mutations in the COL7A1 gene: a 7597G-A transition in exon 107 resulting in a gly2653-to-arg (G2653R) substitution, and a 7411C-T transition in exon 97 resulting in an arg2471-to-ter (R2471X; 120120.0037) substitution. The patient had a severe phenotype, with generalized blistering since birth and skin missing from the left thumb and both feet, whereas the heterozygous parents and younger brother were unaffected.
For discussion of the arg2471-to-ter (R2471X) mutation in the COL7A1 gene that was found in compound heterozygous state in a patient with autosomal recessive epidermolysis bullosa dystrophica (226600) by Christiano et al. (1996), see 120120.0036.
In 2 affected sibs with autosomal recessive epidermolysis bullosa dystrophica (226600), whose parents were consanguineous, Christiano et al. (1996) identified a homozygous 8245G-A transition in the COL7A1 gene, resulting in a gly2749-to-arg (G2749) substitution. The phenotype was severe, with multiple blisters, erosions, scarring, mitten deformities of the hands, and joint contractures. The heterozygous parents were unaffected.
In affected members of a 3-generation family with autosomal dominant transient bullous dermolysis of the newborn (131705), Christiano et al. (1997) identified a heterozygous G-to-C transversion in the last nucleotide of intron 35 of the COL7A1 gene, resulting in the skipping of exon 36. The family had previously been reported by Fine et al. (1993).
In 2 unrelated patients, one with dystrophic epidermolysis bullosa inversa (see 226600) and the other with classic severe recessive dystrophic epidermolysis bullosa (226600), Hovnanian et al. (1994) identified a heterozygous C-to-T transition in exon 6 of the COL7A1 gene, resulting in an arg109-to-ter (R109X) substitution. An unaffected parent of each of the patients was also heterozygous for the mutation. A second pathogenic mutation in the COL7A1 gene was not observed in either patient, but Hovnanian et al. (1994) presented convincing evidence that the disorder showed autosomal recessive inheritance.
In 2 brothers with autosomal recessive dystrophic epidermolysis bullosa inversa (see 226600), Kahofer et al. (2003) identified compound heterozygosity for 2 mutations in the COL7A1 gene: a 6205C-T transition in exon 74 resulting in an arg2069-to-cys (R2069C) substitution, and a 425A-G transition in exon 3 resulting in a lys142-to-arg (K142R; 120120.0045) substitution. Each unaffected parent was heterozygous for 1 of the mutations. Computer modeling suggested that the 425A-G mutation may affect splicing.
For discussion of the gly2316-to-arg (G2316R) mutation in the COL7A1 gene that was found in compound heterozygous state in a patient with epidermolysis bullosa dystrophica (226600) by Shimizu et al. (1999), see 120120.0023.
For discussion of the gln2827-to-ter (Q2827X) mutation in the COL7A1 gene that was found in compound heterozygous state in a patient with epidermolysis bullosa dystrophica (226600) by Sato-Matsumura et al. (2002), see 120120.0024.
In a proband and his father and paternal grandfather with transient bullous dermolysis of the newborn (131705), Fassihi et al. (2005) identified heterozygosity for a 4565G-A transition in exon 45 of the COL7A1 gene, resulting in a gly1522-to-glu (G1522E) substitution.
For discussion of the lys142-to-arg (K142R) mutation in the COL7A1 gene that was found in compound heterozygous state in a patient with epidermolysis bullosa dystrophica inversa (see 226600) by Kahofer et al. (2003), see 120120.0041.
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