Glycine Substitution Mutations in the Type VII Collagen Gene (COL7A1) in Dystrophic Epidermolysis Bullosa: Implications for Genetic Counseling

Kon, Atsushi; McGrath, John A.; Pulkkinen, Leena; Nomura, Kazuo; Nakamura, Takehiko; Maekawa, Yoshihiro; Christiano, Angela M.; Hashimoto, Isao; Uitto, Jouni

doi:10.1111/1523-1747.ep12335324

Cited by 43 publications

(27 citation statements)

References 18 publications

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“…Fig. Substitution mutations in the triple-helix region, especially the substitution of glycine residues in Gly-X-Y repeats, are the characteristic molecule bases underlying the pathogenesis of DDEB (22). Of the splicing site mutation, all are found in the triple helical region, and most of them locate in the 3 ' end region of exon 87 or near the donor site of intron 87, probably resulting in the in-frame skipping of exon 87 (3,16,17).…”

Section: Discussionmentioning

confidence: 99%

Genotype–Phenotype Correlation in Chinese Patients with Dystrophic Epidermolysis Bullosa Pruriginosa

Jiang

Sun²,

Lei³

2012

Acta Derm Venerol

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Dystrophic epidermolysis bullosa pruriginosa (DEB-Pr) is a rare variant of dystrophic epidermolysis bullosa (DEB) due to dominant or recessive mutations in the COL7A1 gene. More than 40 mutations in COL7A1 have been described in DEB-Pr. The aim of this study was to understand the genotype-phenotype correlation in Chinese patients with DEB-Pr. Three Chinese families with typical clinical features of DEB-Pr were studied. The results were analysed in association with the eight Chinese DEB-Pr patients reported in the literature. In the three Chinese families with DEB-Pr, we found two dominant cases with G1773R and c.6900+1G>C mutations, and one case with heterozygous G2701W mutation of uncertain inheritance mode. In the 10 Chinese patients with dominant type of DEB-Pr, 7 glycine substitutions and three splicing site mutations of exon 87 skipping were identified. Glycine substitution mutations in the triple helix region and exon 87 skipping, leading to the in-frame deletion of 23 amino acid residues in the triple-helix, are often seen in Chinese patients with dominant DEB-Pr, although the glycine substitutions are also frequently present in dominant DEB.

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Section: Discussionmentioning

confidence: 99%

Genotype–Phenotype Correlation in Chinese Patients with Dystrophic Epidermolysis Bullosa Pruriginosa

Jiang

Sun²,

Lei³

2012

Acta Derm Venerol

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“…Such mutations include G1782R, G2749R, G2569R, G2653R, and G2674R (20); G2575R (15,38); G1982W, G2025A, and G2049E (38); G1347R (39); and G2671V (40).…”

Section: Discussionmentioning

confidence: 99%

“…Primers used for amplification of exon 73 were as follows: sense primer, 5Ј-GGGTGTAGCTGTACAGC-CAC-3Ј (nucleotides 23399 -23419); and antisense primer, 5Ј-CCCTCT-TCCCTCACTCTCCT-3Ј (nucleotides 23684 -23704) (20). For PCR, 100 ng of genomic DNA were used as template, and amplification conditions were 95°C for 2 min, followed by 40 The pedigrees of the families 1-3 demonstrate dominant inheritance of the respective mutations. A, family 1; B, family 2; C, family 3.…”

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confidence: 99%

Some, but Not All, Glycine Substitution Mutations inCOL7A1 Result in Intracellular Accumulation of Collagen VII, Loss of Anchoring Fibrils, and Skin Blistering

Hammami-Hauasli¹,

Schumann²,

Raghunath³

et al. 1998

Journal of Biological Chemistry

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COL7A1 gene mutations cause dystrophic epidermolysis bullosa, a skin blistering disorder. The phenotypes result from defects of collagen VII, the major component of the anchoring fibrils at the dermo-epidermal junction; however, the molecular mechanisms underlying the phenotypes remain elusive. We investigated naturally occurring COL7A1 mutations and showed that some, but not all, glycine substitutions in collagen VII interfered 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. Limited proteolytic digestions of mutant procollagen VII produced aberrant fragments and revealed reduced stability of the triple helix. 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. These data demonstrate that collagen VII presents a remarkable exception among collagens in that not all glycine substitutions within the triple helix exert dominant-negative interference and that the biological consequences of the substitutions probably depend on their position within the triple helix.Anchoring fibrils attach the epidermal basement membrane of the skin to the underlying dermal connective tissue (1, 2). They represent polymers of collagen VII, a large homotrimeric protein with a central triple helix and flanking amino-and carboxyl-terminal globular domains. Epidermal keratinocytes synthesize and secrete collagen VII as a triple helical precursor (procollagen VII) into the extracellular matrix. After secretion, procollagen VII undergoes proteolytic trimming to collagen VII (3) and assembles to polymers (1). This is a multistep process during which collagen VII monomers first form disulfidebonded antiparallel dimers and then laterally aggregate into anchoring fibrils, which interact with laminin 5 to secure the dermo-epidermal adhesion (1, 4). Further stabilization of anchoring fibrils and presumably of intermolecular aggregates is achieved through cross-linking by transglutaminase-2 (5). Anchoring fibrils are functionally deficient in hereditary dystrophic epidermolysis bullosa (DEB), 1 a heterogeneous group of bullous skin disorders (for reviews, see Refs. 6 and 7) with mechanically induced blistering and scarring of the skin. In the most severe forms of the disease, both collagen VII protein and anchoring fibrils are absent from the skin (8), whereas in milder forms, collagen VII is expressed, but the morphology of the anchoring fibrils may be altered (7, 9).Mutations in COL7A1 encoding collagen VII have been disclosed in both recessive and dominant DEB subtypes (10 -17). In reces...

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“…1). [14][15][16][17][18][19][20][21][22][23][24][25][26][27] In this study we investigated the molecular basis of DEB in two affected families, one from Mexico and one from Scotland, using polymerase chain reaction (PCR) amplification of genomic DNA, heteroduplex analysis, direct automated sequencing of PCR products displaying heteroduplex bandshifts and verification of mutations by restriction endonuclease digestion. [14][15][16][17][18][19][20][21][22][23][24][25][26][27] In this study we investigated the molecular basis of DEB in two affected families, one from Mexico and one from Scotland, using polymerase chain reaction (PCR) amplification of genomic DNA, heteroduplex analysis, direct automated sequencing of PCR products displaying heteroduplex bandshifts and verification of mutations by restriction endonuclease digestion.…”

Section: Discussionmentioning

confidence: 99%

A recurrent glycine substitution mutation, G2043R, in the type VII collagen gene (COL7A1) in dominant dystrophic epidermolysis bullosa

Mellerio

Salas‐Alanís

Talamantes

et al. 1998

British Journal of Dermatology

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Dystrophic epidermolysis bullosa (DEB) is caused by mutations in the type VII collagen gene (COL7A1). Nearly all cases of dominant DEB are caused by glycine substitution mutations occurring within the triple helical region of type VII collagen, and most of the mutations are unique to individual families. In this study, we identified a patient of Hispanic-Mexican origin with a mild form of DEB, which resulted from a de novo dominant glycine substitution, G2043R, in exon 73 of COL7A1. We also investigated a Scottish family with a three-generation pedigree of dominant DEB, in whom the same glycine to arginine substitution mutation was demonstrated. This particular mutation has also been detected previously in three other families with dominant DEB: one Italian, one Hungarian and one Norwegian. Given the widespread geographical distribution of this mutation and the demonstration of its occurrence as a de novo event, G2043R therefore represents the first example of a mutational hotspot in dominant DEB. Interestingly, although both the Mexican and Scottish families we studied had some clinical features in keeping with the Pasini form of the disorder, there was considerable interfamilial variability as well as intrafamilial diversity in the affected individuals.

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Glycine Substitution Mutations in the Type VII Collagen Gene (COL7A1) in Dystrophic Epidermolysis Bullosa: Implications for Genetic Counseling

Cited by 43 publications

References 18 publications

Genotype–Phenotype Correlation in Chinese Patients with Dystrophic Epidermolysis Bullosa Pruriginosa

Genotype–Phenotype Correlation in Chinese Patients with Dystrophic Epidermolysis Bullosa Pruriginosa

Some, but Not All, Glycine Substitution Mutations inCOL7A1 Result in Intracellular Accumulation of Collagen VII, Loss of Anchoring Fibrils, and Skin Blistering

A recurrent glycine substitution mutation, G2043R, in the type VII collagen gene (COL7A1) in dominant dystrophic epidermolysis bullosa

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