Evidence for a de novo, dominant germ-line mutation causative of osteogenesis imperfecta in two Red Angus calves

A genetic disorder, osteogenesis imperfecta (OI) is broadly characterized by connective tissue abnormalities and bone fragility most commonly attributed to alterations in Type I collagen. Two Red Angus calves by the same sire presented with severe bone and dental fragility, blue sclera, and evidence...

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Bibliographic Details
Published in:Mammalian genome 2019-04, Vol.30 (3-4), p.81-87
Main Authors: Petersen, Jessica L., Tietze, Shauna M., Burrack, Rachel M., Steffen, David J.
Format: Article
Language:English
Subjects:
Alleles
Animal Genetics and Genomics
Animals
Biomedical and Life Sciences
Cattle
Cattle Diseases - genetics
Cattle Diseases - metabolism
Cell Biology
Collagen
Collagen (type I)
Collagen Type I - genetics
Collagen Type I - metabolism
Female
Fractures
Genes, Dominant
Genetic disorders
Genomes
Genotypes
Germ-Line Mutation
Glycine
Human Genetics
Life Sciences
Livestock
Male
Missense mutation
Mutation
Mutation, Missense
Osteogenesis
Osteogenesis imperfecta
Osteogenesis Imperfecta - genetics
Osteogenesis Imperfecta - metabolism
Osteogenesis Imperfecta - veterinary
Paternity
Pedigree
Phenotype
Phenotypes
Semen
Serine
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Summary:A genetic disorder, osteogenesis imperfecta (OI) is broadly characterized by connective tissue abnormalities and bone fragility most commonly attributed to alterations in Type I collagen. Two Red Angus calves by the same sire presented with severe bone and dental fragility, blue sclera, and evidence of in utero fractures consistent with OI congenita. Comparative analyses with human cases suggested the OI in these calves most closely resembled that classified as OI Type II. Due to the phenotypic classification and shared paternity, a dominant, germ-line variant was hypothesized as causative although recessive genotypes were also considered due to a close relationship between the sire and dam of one calf. Whole-genome sequencing revealed the presence of a missense mutation in the alpha 1 chain of collagen Type I ( COL1A1 ), for which both calves were heterozygous. The variant resulted in the substitution of a glycine residue with serine in the triple helical domain of the protein; in this region, glycine normally occupies every third position as is critical for correct formation of the Type I collagen molecule. Allele-specific amplification by droplet digital PCR further quantified the variant at a frequency of nearly 4.4% in the semen of the sire while it was absent in his blood, supporting the hypothesis of a de novo causative variant for which the germ line of the sire was mosaic. The identification of novel variants associated with unwanted phenotypes in livestock is critical as the high prolificacy of breeding stock has the potential to rapidly disseminate undesirable variation.
ISSN:0938-8990
1432-1777
DOI:10.1007/s00335-019-09794-4