Osteogenesis imperfecta in a male holstein calf associated with a possible oligogenic origin

• Published in: The Veterinary quarterly 2020-01, Vol.40 (1), p.58-67
• Main Authors: Zhang, Xuying, Hirschfeld, Marc, Beck, Julia, Kupke, Alexandra, Köhler, Kernt, Schütz, Ekkehard, Brenig, Bertram
• Format: Article
• Language: English
• Subjects: Abnormalities; Animals; Anomalies; Autopsy; Bone diseases; Bovine; brittle bone disease; Calves; Case-Control Studies; Cattle; Cattle Diseases - genetics; Cattle Diseases - pathology; congenital bone disorder; cow; Domestic animals; Embryo transfer; Fractures; Fragility; Gene sequencing; Genes; Genetic analysis; Genetic Predisposition to Disease - genetics; Genomes; Genotype; Hearing loss; Hypercalciuria; Male; Males; malformation; Multifactorial Inheritance; Mutation; Mutation - genetics; Neonates; osteodysplasia; osteodystrophy; Osteogenesis; Osteogenesis imperfecta; Osteogenesis Imperfecta - genetics; Osteogenesis Imperfecta - pathology; Osteogenesis Imperfecta - veterinary; Osteopenia; Signs and symptoms
• ISSN: 0165-2176; 1875-5941
• DOI: 10.1080/01652176.2020.1721611

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