Letko Anna, Harkema Liesbeth, Peterson Karianne, Dijkman Reinie, Drögemüller Cord
Institute of Genetics, Vetsuisse Faculty, University of Bern, 3012, Bern, Switzerland.
Department of Pathology, Royal Animal Health Services (GD), P.O. Box 9, 7400 AA, Deventer, The Netherlands.
J Appl Genet. 2025 Mar 18. doi: 10.1007/s13353-025-00957-5.
Epidermolysis bullosa (EB) is a group of inherited skin disorders characterized by skin fragility and blistering. Here, four Bleu du Maine lambs, sired by one ram, were diagnosed with EB very early in life. Due to the severity of the clinical signs, the lambs had to be euthanized. The affected lambs exhibited hoof sloughing and multiple ulcerations on the head, oral cavity, skin over the joints, and the ruminal pillars. Histopathology showed abrupt subepidermal clefts, epidermal detachment directly above the basal membrane, and ulcerations consistent with junctional EB (JEB). Two cases underwent whole-genome sequencing (WGS) to identify the genetic cause. Genomic analyses with the hypothesis of autosomal recessive inheritance identified the most likely pathogenic homozygous 1-bp deletion in the LAMB3 gene (NC_056065.1:g.73166198delG). Recessive forms of JEB in humans and dogs are caused by variants in LAMB3 gene, which encodes β3 subunit of laminin 332, a critical component of the epidermal basal membrane. The ovine frameshift variant putatively introduces a premature stop codon and disrupts the donor splice site of exon 20. The variant allele was homozygous in both sequenced cases and heterozygous in three unaffected close relatives and was absent in 1075 unrelated control sheep of various other breeds. This study highlights the importance of genetic investigation in veterinary diagnostics of and represents the first report of a LAMB3-related recessive EB in sheep. The findings enable genetic testing to inform breeding strategies and provide a second spontaneous large animal model for LAMB3-related JEB in humans.
大疱性表皮松解症（EB）是一组遗传性皮肤病，其特征为皮肤脆弱和水疱形成。在此，由一只公羊所生的四只蓝缅因州羔羊在生命早期就被诊断出患有EB。由于临床症状严重，这些羔羊不得不实施安乐死。患病羔羊出现蹄部脱落，头部、口腔、关节处皮肤以及瘤胃支柱上有多处溃疡。组织病理学显示表皮下突然出现裂隙，基底膜上方的表皮分离，以及与交界性EB（JEB）相符的溃疡。两例进行了全基因组测序（WGS）以确定遗传病因。基于常染色体隐性遗传假说的基因组分析确定，LAMB3基因（NC_056065.1:g.73166198delG）中最可能致病的纯合1个碱基缺失。人类和犬类的隐性JEB形式由LAMB3基因的变异引起，该基因编码层粘连蛋白332的β3亚基，是表皮基底膜的关键成分。绵羊的移码变异可能引入一个提前终止密码子，并破坏外显子20的供体剪接位点。在两个测序病例中，变异等位基因是纯合的，在三个未受影响的近亲中是杂合的，在1075只其他品种的无关对照绵羊中不存在。本研究强调了基因调查在兽医诊断中的重要性，并代表了绵羊中与LAMB3相关的隐性EB的首次报道。这些发现使基因检测能够为育种策略提供信息，并为人类中与LAMB3相关的JEB提供第二个自发的大型动物模型。
