Categories: Skeleton phene (incl. short stature & teeth)

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 166210 (trait) , 120150 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal dominant

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2017

Molecular basis: Bourneuf et al. (2017): a de novo likely causal variant is COL1A1 p.1049_1050delinsS in Fleckvieh Petersen et al. (2019): "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." Jacinto et al. (2021): "Genetic analysis ["an OI type II-affected neonatal Holstein calf"] revealed a private heterozygous missense variant in COL1A1 (c.3917T>A) located in the fibrillar collagen NC1 domain (p.Val1306Glu) that most likely occurred de novo. This confirmed the diagnosis of OI type II and represents the first report of a pathogenic variant in the fibrillar collagen NC domain of COL1A1 associated to OI type II in domestic animals."

Clinical features: Petersen et al. (2019): "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."

Pathology: Petersen et al. (2019): "Microscopically, osteopenia was observed at the distal femoral metaphysis. Trabeculae of primary spongiosa were thin, delicate, and covered by very narrow seams of osteoid. The remodeling was delayed with primary spongiosia extending deeper into the cortex than normal. Microfractures were noted at the juncture between primary and secondary spongiosa in the proximal femoral sample from the bull calf. The osteoid lamella of the femoral cortices was thin and the periosteum was thickened. Dentin and enamel appeared thin."

Breeds: Holstein (black and white) (Cattle) (VBO_0000237), Red Angus (Cattle) (VBO_0000350), Simmental (Cattle) (VBO_0000380).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: