Department of Veterinary Medical Sciences, University of Bologna, 40064 Ozzano Emilia, Italy.
Institute of Genetics, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland.
Genes (Basel). 2021 Nov 12;12(11):1792. doi: 10.3390/genes12111792.
Inherited channelopathies are a clinically and heritably heterogeneous group of disorders that result from ion channel dysfunction. The aim of this study was to characterize the clinicopathologic features of a Belgian Blue x Holstein crossbred calf with paradoxical myotonia congenita, craniofacial dysmorphism, and myelodysplasia, and to identify the most likely genetic etiology. The calf displayed episodes of exercise-induced generalized myotonic muscle stiffness accompanied by increase in serum potassium. It also showed slight flattening of the splanchnocranium with deviation to the right side. On gross pathology, myelodysplasia (hydrosyringomielia and segmental hypoplasia) in the lumbosacral intumescence region was noticed. Histopathology of the muscle profile revealed loss of the main shape in 5.3% of muscle fibers. Whole-genome sequencing revealed a heterozygous missense variant in affecting an evolutionary conserved residue (p.Trp416Cys). The mutation was predicted to be deleterious and to alter the pore helix of the ion transport domain of the transmembrane protein. The identified variant was present only in the affected calf and not seen in more than 5200 other sequenced bovine genomes. We speculate that the mutation occurred either as a parental germline mutation or post-zygotically in the developing embryo. This study implicates an important role for as a member of the potassium voltage-gated channel group in neurodegeneration. Providing the first possible -related disease model, we have, therefore, identified a new potential candidate for related conditions both in animals and in humans. This study illustrates the enormous potential of phenotypically well-studied spontaneous mutants in domestic animals to provide new insights into the function of individual genes.
遗传性通道病是一组临床和遗传上具有异质性的疾病，其特征是离子通道功能障碍。本研究旨在描述一头具有反常性先天性肌强直、颅面畸形和骨髓发育不良的比利时蓝牛与荷斯坦牛杂交犊牛的临床病理特征，并确定最可能的遗传病因。该犊牛表现出运动诱发的全身性肌强直伴血清钾升高的发作。它还表现出轻微的颅面骨扁平，向右侧偏斜。大体病理学检查发现，腰骶部膨隆区存在脊髓积水和节段性发育不良。肌肉剖面图的组织病理学检查显示，5.3%的肌纤维失去了主要形状。全基因组测序显示，在 中发现了一个杂合错义变异，影响了一个进化保守的残基（p.Trp416Cys）。该突变被预测为有害的，会改变跨膜蛋白的离子转运域的孔螺旋。该鉴定出的变异仅存在于受影响的犊牛中，而在 5200 多个其他测序的牛基因组中未发现。我们推测该突变要么是亲本生殖系突变，要么是在发育中的胚胎中发生的合子后突变。本研究表明 在神经退行性变中作为钾电压门控通道家族的一个重要成员发挥作用。作为首例可能与 相关的疾病模型，我们因此确定了一个新的潜在候选基因，用于研究动物和人类的相关疾病。本研究说明了表型研究良好的家畜自发性突变体在提供对单个基因功能的新见解方面具有巨大的潜力。
