Osteogenesis imperfecta, type II (COL1A1-related)

 

Gene: COL1A1

Transmission: Autosomal dominant

For an autosomal dominant genetic disease, an animal must have at least one copy of the mutation in question to be at risk of developing the disease.  One or both of the parents of an animal with the mutation is a carrier of the mutation, or the mutation can be de novo.

Mutations:

Simmental mutation: Deletion, COL1A1 gene: c.3145_3148 del.T, p.(Ala1049_Pro1050 del.S), Chr.19.

Angus mutation: Substitution, COL1A1 gene: c.1063G>A, c.(Gly355Ser), Chr.19.

Holstein mutation: Substitution, COL1A1 gene: c.3917T>A. c.(Val1306Glu), Chr.19.

Normande mutation: Substitution, COL1A1 gene: c.4234G>A, c.(Asp1412Asn), Chr.19.

Medical system: Skeletal

Breeds: Simmental, Angus, Holstein, Normande

Age of onset of symptoms: At birth

Collagen type 1 is an important extracellular structural protein found in cartilage and bone. It is composed of a triple helix of fibrillar proteins coded for by the COL1A1a d COL1A2 genes.  Mutations in either of these genes can result in osteogenesis imperfecta, sometimes called brittle bone disease, in several species.  This usually presents as a dominant genetic disease due to de novo mutations or inherited from non-symptomatic mosaic parents.   Symptoms of a severe and usually lethal form, osteogenesis imperfecta type II, are evident at birth and include bone fragility with peri-natal and prenatal bone fractures, long bone deformity and poor mineralization of bone.

Cases of osteogenesis imperfecta type II in several cattle breeds have recently been characterized at the molecular level.  In each case, heterozygous mutations in the COL1A1 gene were identified.  When the mutations are de novo in an offspring issued from normal parents, the disease is self-limiting as it is peri-natal lethal.  If the mutation is germline in a normal parent or if the parent is mosaic, the situation is more problematic, particularly if it involves a bull used for artificial insemination.  This was the case for a Fleckvieh (Simmental) bull named Halvar PP, where 29% of his offspring were diagnosed with osteogenesis imperfecta type II, and where 4.4% of his spermatozoa carried the causal mutation.  Similarly, in the Normand breed, an insemination bull named Ly fathered at least 17 calves that diagnosed with osteogenesis imperfecta type II.  In this case, about 6% of his spermatozoa on average carried the causal mutation.  Good reproductive records in insemination centers and at calving are necessary to identify such cases of problematic bulls and to stop the use of their semen.

 

References:

OMIA link: [2127-9913]

Corbeau J, Grohs C, Jourdain J, et al. (2024) A recurrent de novo missense mutation in COL1A1 causes osteogenesis imperfecta type II and preterm delivery in Normande cattle. Genet Sel Evol 56:39.  [pm/38773368]

Jacinto JGP, Häfliger IM, McEvoy FJ, Drögemüller C, Agerholm JS. (2021) A de novo mutation in COL1A1 in a Holstein calf with osteogenesis imperfecta type II. Animals (Basel) 11:561.  [pm/33672767]

Petersen JL, Tietze SM, Burrack, RM, et al. (2019) Evidence for a de novo, dominant germ-line mutation causative of osteogenesis imperfecta in two Red Angus calves. Mamm Genome 30:81-87.  [30788588]

Bourneuf E, Otz P, Pausch H, et al. (2017) Rapid discovery of de novo deleterious mutations in cattle enhances the value of livestock as model species. Sci Rep 7:11466. [pm/28904385]

 

With contributions by: Laurianne D’Ambroise and Loïc Sicotte, Class of 2030, Faculty of Veterinary Medicine, University of Montreal.  (Translation: DWS).