Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
Clinic for Ruminants, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
BMC Vet Res. 2022 Jan 7;18(1):20. doi: 10.1186/s12917-021-03113-3.
Ichthyosis describes a localized or generalized hereditary cornification disorder caused by an impaired terminal keratinocyte differentiation resulting in excessive stratum corneum with the formation of more or less adherent scales. Ichthyosis affects humans and animals. Two rare bovine forms are reported, the severe harlequin ichthyosis and the less severe congenital ichthyosis, both characterized by a severe orthokeratotic lamellar hyperkeratosis.
A 2-weeks-old purebred Scottish Highland calf was referred because of a syndrome resembling congenital ichthyosis. The clinical phenotype included diffuse alopecia and a markedly lichenified skin covered with large and excessive scales. Additionally, conjunctivitis and ulceration of the cornea were noted. Post-mortem examination revealed deep fissures in the diffusely thickened tongue and histopathological findings in the skin confirmed the clinical diagnosis. Whole-genome sequencing of the affected calf and comparison of the data with control genomes was performed. A search for private variants in known candidate genes for skin phenotypes including genes related with erosive and hyperkeratotic lesions revealed a single homozygous protein-changing variant, DSP: c.6893 C>A, or p.Ala2298Asp. The variant is predicted to change a highly conserved residue in the C-terminal plakin domain of the desmoplakin protein, which represents a main intracellular component of desmosomes, important intercellular adhesion molecules in various tissues including epidermis. Sanger sequencing confirmed the variant was homozygous in the affected calf and heterozygous in both parents. Further genotyping of 257 Scottish Highland animals from Switzerland revealed an estimated allele frequency of 1.2%. The mutant allele was absent in more than 4800 controls from various other cattle breeds.
This study represents the first report of combined lesions compatible with congenital ichthyosis, alopecia, acantholysis of the tongue and corneal defects associated with a DSP missense variant as the most likely underlying cause. To the best of our knowledge, this study is also the first report of a DSP-related syndromic form of congenital ichthyosis in domestic animals. The results of our study enable genetic testing to avoid the unintentional occurrence of further affected cattle. The findings were added to the Online Mendelian Inheritance in Animals (OMIA) database (OMIA 002243-9913).
鱼鳞病描述了一种局部或全身性遗传性角化障碍，由终末角质形成细胞分化受损引起，导致过度角质层形成，形成或多或少附着的鳞片。鱼鳞病影响人类和动物。据报道，有两种罕见的牛形式，即严重的 Harlequin 鱼鳞病和较轻的先天性鱼鳞病，两者均表现为严重的正角化层状过度角化。
一只 2 周龄的纯种苏格兰高地小牛因类似于先天性鱼鳞病的综合征而被转诊。临床表型包括弥漫性脱发和明显苔藓化的皮肤，覆盖着大而过多的鳞片。此外，还注意到结膜炎和角膜溃疡。尸检显示弥漫性增厚的舌有深裂，皮肤的组织病理学发现证实了临床诊断。对受影响的小牛进行全基因组测序，并将数据与对照基因组进行比较。对包括与侵蚀性和过度角化病变相关的基因在内的已知候选皮肤表型基因中的私有变异进行搜索，发现了一个单一的纯合蛋白改变变异，DSP：c.6893 C>A 或 p.Ala2298Asp。该变体预计会改变桥粒蛋白 desmoplakin 的 C 末端板层素结构域中的高度保守残基，桥粒蛋白是各种组织包括表皮中重要的细胞间黏附分子的主要细胞内成分。Sanger 测序证实该变体在受影响的小牛中为纯合子，在父母双方中为杂合子。对来自瑞士的 257 只苏格兰高地动物进行进一步基因分型显示，估计等位基因频率为 1.2%。在来自其他各种牛品种的 4800 多个对照中，突变等位基因不存在。
本研究首次报道了与先天性鱼鳞病、脱发、舌表浅性松解和角膜缺陷相关的联合病变，最有可能的潜在原因是 DSP 错义变异。据我们所知，这也是在家畜中首次报道与 DSP 相关的先天性鱼鳞病综合征形式。我们的研究结果使遗传测试能够避免意外出现更多受影响的牛。研究结果被添加到在线孟德尔遗传在动物（OMIA）数据库（OMIA 002243-9913）中。
