A recurrent de novo missense mutation in COL1A1 causes osteogenesis imperfecta type II and preterm delivery in Normande cattle

作者：Julien Corbeau, Cécile Grohs, Jeanlin Jourdain, Mekki Boussaha, F. Besnard, Anne Barbat, Vincent Plassard, Julie Rivière, Christophe Hamelin, Jérémy Mortier, Didier Boichard, Raphaël R. Guatteo, Aurélien Capitan · 发表于：Genetics Selection Evolution · 年份：2024 · DOI：10.1186/s12711-024-00909-3 · 被引用次数：6 · 研究领域：Connective tissue disorders research、Bone fractures and treatments、Heterotopic Ossification and Related Conditions

BACKGROUND: Nine male and eight female calves born to a Normande artificial insemination bull named "Ly" were referred to the French National Observatory of Bovine Abnormalities for multiple fractures, shortened gestation, and stillbirth or perinatal mortality. RESULTS: Using Illumina BovineSNP50 array genotypes from affected calves and 84 half-sib controls, the associated locus was mapped to a 6.5-Mb interval on chromosome 19, assuming autosomal inheritance with germline mosaicism. Subsequent comparison of the whole-genome sequences of one case and 5116 control genomes, followed by genotyping in the affected pedigree, identified a de novo missense substitution within the NC1 domain of the COL1A1 gene (Chr19 g.36,473,965G > A; p.D1412N) as unique candidate variant. Interestingly, the affected residue was completely conserved among 243 vertebrate orthologs, and the same substitution in humans has been reported to cause type II osteogenesis imperfecta (OI), a connective tissue disorder that is characterized primarily by bone deformity and fragility. Moreover, three COL1A1 mutations have been described to cause the same syndrome in cattle. Necropsy, computed tomography, radiology, and histology confirmed the diagnosis of type II OI, further supporting the causality of this variant. In addition, a detailed analysis of gestation length and perinatal mortality in 1387 offspring of Ly and more than 160,000 progeny of 63 control bulls allowed us to statistically confirm in a large pe...