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.

中文翻译：

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常染色体隐性表皮松解性大疱性单纯疱疹中的双等位基因KRT5突变，包括完整的人角蛋白5“敲除”。

由于KRT5或KRT14中的单等位基因功能获得性突变，大疱表皮松解症（EBS）通常被遗传为常染色体显性遗传疾病。尽管常染色体隐性形式的EBS与至少10个基因的突变有关，但以前尚未报道由于纯合双等位基因KRT5突变而引起的隐性EBS。据推测，这将导致产前致死率。我们通过执行全外显子组测序（WES）并使用21种基因的EB靶向下一代测序（NGS）面板，在512个不同的EB家族队列中寻找EB的遗传原因。突变的致病性和后果通过表达谱以及组织和超微结构水平来确定。两种致病性 在两名患有EB并发症新生儿死亡的患者中，发现了两名EBS泛型患者的KRT5纯合错义变体和纯合无效突变。在免疫荧光显微镜下，这两个错义突变破坏了角蛋白5的表达，而人类“敲除” KRT5则没有RNA和蛋白质表达。总的来说，这些发现确定了双等位基因KRT5突变的表型范围从轻度，局部性和普遍性到围产期致死，扩大了常染色体隐性EBS的基因型分布。