单纯大疱性表皮松解
错义突变
大疱性表皮松解症
角蛋白5
生物
遗传学
外显子组测序
表型
突变
角蛋白14
基因
转基因
转基因小鼠
作者
Hassan Vahidnezhad,Leila Youssefian,Maryam Daneshpazhooh,Hamidreza Mahmoudi,Ariana Kariminejad,Judith Fischer,Julie Christiansen,Holm Schneider,Alyson Guy,Lu Liu,John A. McGrath,Cristina Has,Jouni Uitto
标识
DOI:10.1016/j.matbio.2019.07.002
摘要
Epidermolysis bullosa simplex (EBS) is usually inherited as an autosomal dominant disease due to monoallelic gain-of-function mutations in KRT5 or KRT14. Although autosomal recessive forms of EBS have been associated with mutations in at least 10 genes, recessive EBS due to homozygous biallelic KRT5 mutations has not been reported previously; it has been hypothesized that it would result in prenatal lethality. We sought the genetic causes of EB in a cohort of 512 distinct EB families by performing whole exome sequencing (WES) and using an EB-targeting next-generation sequencing (NGS) panel of 21 genes. The pathogenicity and consequences of the mutations were determined by expression profiling and at tissue and ultrastructural levels. Two pathogenic, homozygous missense variants of KRT5 in two patients with generalized EBS and a homozygous null mutation in a patient who died as a neonate from complications of EB were found. The two missense mutations disrupted keratin 5 expression on immunofluorescence microscopy, and the human “knock-out” of KRT5 showed no RNA and protein expression. Collectively, these findings identify biallelic KRT5 mutations with a phenotypic spectrum varying from mild, localized and generalized to perinatal lethal, expanding the genotypic profile of autosomal recessive EBS.
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