Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001, Bern, Switzerland.
University of Bern, 3001, Bern, Switzerland.
Mol Genet Genomics. 2022 Jan;297(1):147-154. doi: 10.1007/s00438-021-01842-6. Epub 2021 Dec 8.
Investigations of hereditary phenotypes in spontaneous mutants may help to better understand the physiological functions of the altered genes. We investigated two unrelated domestic shorthair cats with bulbous swellings of the hair shafts. The clinical, histopathological, and ultrastructural features were similar to those in mice with lanceolate hair phenotype caused by loss-of-function variants in Dsg4 encoding desmoglein 4. We sequenced the genomes from both affected cats and compared the data of each affected cat to 61 control genomes. A search for private homozygous variants in the DSG4 candidate gene revealed independent frameshift variants in each case, c.76del or p.Ile26fsLeu4 in case no. 1 and c.1777del or p.His593Thrfs23 in case no. 2. DSG4 is a transmembrane glycoprotein located primarily in the extracellular part of desmosomes, a complex of adhesion molecules responsible for connecting the keratin intermediate filaments of neighbouring epithelial cells. Desmosomes are essential for normal hair shaft formation. Both identified DSG4 variants in the affected cats lead to premature stop codons and truncate major parts of the open-reading frame. We assume that this leads to a complete loss of DSG4 function, resulting in an incorrect formation of the desmosomes and causing the development of defective hair shafts. Together with the knowledge on the effects of DSG4 variants in other species, our data suggest that the identified DSG4 variants cause the hair shaft dystrophy. To the best of our knowledge, this study represents the first report of pathogenic DSG4 variants in domestic animals.
对自发性突变体的遗传表型的研究有助于更好地理解改变基因的生理功能。我们研究了两只不相关的家短毛猫，它们的毛发有球状肿胀。临床、组织病理学和超微结构特征与 Dsg4 编码桥粒芯糖蛋白 4 功能丧失变异导致的披针状毛发表型的小鼠相似。我们对两只受影响的猫进行了基因组测序，并将每只受影响的猫的数据与 61 个对照基因组进行了比较。在 DSG4 候选基因中寻找纯合隐性变异时，发现每只猫都有独立的移码变异，在病例 1 中为 c.76del 或 p.Ile26fsLeu4，在病例 2 中为 c.1777del 或 p.His593Thrfs23。DSG4 是一种跨膜糖蛋白，主要位于桥粒的细胞外部分，桥粒是一种连接相邻上皮细胞角蛋白中间丝的黏附分子复合物。桥粒对于正常毛发的形成是必不可少的。受影响的猫中的两种 DSG4 变异都导致了提前终止密码子的出现，并截断了开放阅读框的主要部分。我们假设这导致了 DSG4 功能的完全丧失，导致桥粒的形成不正确，并导致毛发的发育缺陷。结合其他物种中 DSG4 变异的影响，我们的数据表明，鉴定出的 DSG4 变异导致了毛发的营养不良。据我们所知，这项研究是首次在家畜中发现致病性 DSG4 变异。
