Abstract

Background: Neuromusculoskeletal anomalies generally in combination with severe clinical symptoms, comprise a heterogeneous group of fairly common and mostly fatal disorders in man and animals. Osteogenesis imperfecta (OI), also known as brittle bone disease, causes bone fragility and deformity. Prominent extra-skeletal accessory manifestations of OI comprise blue/gray sclerae, hearing impairment, lung abnormalities and hypercalciuria. Cases of OI in cattle have been reported. However, no causative mutations have been identified in cattle so far.

Aim: To report a possible oligogenic origin identified in a calf from clinically healthy parents suffering from OI.

Materials and Methods: A neonatal embryo transfer male Holstein calf developing multiple fractures with bone tissue showing marked osteopenia was used for whole genome re-sequencing as well as its parents. In addition, 2,612 randomly chosen healthy Holstein cattle were genotyped as well as controls.

Results: Sixteen candidate genes with potential protein-altering variants were selected revealing non-synonymous variants only within IFITM5 and CRTAP genes. However, in-depth gene analysis did not result in the identification of a single causative mutation in the OI calf.

Conclusion: The analysis of the OI case revealed a possible oligogenic origin of the disease attributable to additive effects of three candidate genes, i.e., ABCA13, QRFPR, and IFTIM5.

Clinical relevance: Most OI cases in humans and domestic animals reported so far are caused by distinct dominant or recessive monogenic mutations, therefore a potential oligogenic additive genetic effect is a novel finding. Furthermore, the case presented here demonstrates that cross-species genetic analyses might not always be straightforward.

摘要

背景：神经肌肉骨骼异常通常与严重的临床症状相结合，在人和动物中包括相当常见且主要是致命性疾病的异质性组。成骨不全症（OI），也称为脆性骨病，会导致骨骼脆弱和畸形。OI的突出的骨骼外辅助表现包括蓝色/灰色巩膜，听力障碍，肺部异常和高钙尿。据报道，牛OI病例。但是，到目前为止，尚未在牛中鉴定出致病突变。

目的：报告在犊牛中从临床健康的患有OI的父母那里鉴定出的可能的寡聚起源。

材料和方法：将新生的胚胎移植雄性荷斯坦牛犊发育成多处骨折，骨组织显示出明显的骨质减少，并对其父母进行全基因组重测序。另外，对2612只随机选择的健康荷斯坦牛进行了基因分型，并进行了对照。

结果：选择了16个具有潜在蛋白质改变变体的候选基因，仅在IFITM5和CRTAP基因内揭示了非同义变体。但是，深入的基因分析未发现OI小牛的单个致病突变。

结论：对OI病例的分析显示，该疾病的可能是寡聚起源，可能归因于三个候选基因ABCA13，QRFPR和IFTIM5的累加作用。

临床意义：迄今为止报道的大多数人和家畜的OI病例是由明显的显性或隐性单基因突变引起的，因此潜在的寡聚加成遗传效应是一个新发现。此外，这里介绍的案例表明，跨物种遗传分析可能并不总是很简单。