Kon A, McGrath J A, Pulkkinen L, Nomura K, Nakamura T, Maekawa Y, Christiano A M, Hashimoto I, Uitto J
Department of Dermatology and Cutaneous Biology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
J Invest Dermatol. 1997 Feb;108(2):224-8. doi: 10.1111/1523-1747.ep12335324.
Dystrophic epidermolysis bullosa (DEB) is an inherited mechanobullous disorder characterized by fragility of the skin and mucous membranes. The anchoring fibril protein, type VII collagen, is encoded by COL7A1, which harbors mutations in this group of diseases. In this study, we report novel glycine substitution mutations in COL7A1 in two Japanese families with DEB. The mutation detection strategy consisted of PCR amplification of genomic DNA, followed by heteroduplex analysis and nucleotide sequencing of the PCR products demonstrating altered mobility. The first case is a patient with clinically severe recessive DEB. The proband was shown to have a homozygous glycine-to-valine substitution (G2671V) in exon 108. The clinically unaffected parents were heterozygous carriers of this mutation, indicating that this glycine substitution in one allele is "silent" when combined with a normal COL7A1 allele. Thus, this patient appeared to be affected with DEB inherited in an autosomal recessive pattern. The second case was a DEB patient with a heterozygous glycine-to-glutamic acid substitution (G2079E) in exon 75. The parents were clinically unaffected and neither had this mutation in their peripheral blood leukocyte DNA. Haplotype analyses suggested that this case arose as a de novo occurrence of autosomal dominant DEB. These cases illustrate the consequences of COL7A1 glycine substitution mutations underlying DEB in terms of the mode of inheritance and the phenotype, with profound implications for genetic counseling of individuals at risk for recurrence of DEB in subsequent offspring or future generations.
营养不良性大疱性表皮松解症（DEB）是一种遗传性机械性大疱性疾病，其特征为皮肤和黏膜脆弱。锚定原纤维蛋白VII型胶原蛋白由COL7A1编码，该基因在这类疾病中存在突变。在本研究中，我们报告了两个日本DEB家族中COL7A1新的甘氨酸替代突变。突变检测策略包括对基因组DNA进行PCR扩增，随后进行异源双链分析以及对显示迁移率改变的PCR产物进行核苷酸测序。第一例是一名临床症状严重的隐性DEB患者。先证者在第108外显子中被检测到纯合的甘氨酸到缬氨酸替代（G2671V）。临床无症状的父母是该突变的杂合携带者，这表明当一个等位基因中的这种甘氨酸替代与正常的COL7A1等位基因结合时是“沉默”的。因此，这名患者似乎患有常染色体隐性遗传模式的DEB。第二例是一名DEB患者，在第75外显子中有杂合的甘氨酸到谷氨酸替代（G2079E）。其父母临床无症状，外周血白细胞DNA中均无此突变。单倍型分析表明，该病例是常染色体显性DEB的新发病例。这些病例说明了COL7A1甘氨酸替代突变在DEB中的遗传模式和表型方面的后果，对有DEB复发风险的个体在后续后代或未来世代的遗传咨询具有深远意义。
