Dental, skeletal, retinal atrophy, DSRA (MIA3-related)

Gene: MIA3

Transmission: Autosomal recessive

For an autosomal recessive genetic disease an animal must have two copies of the mutation in question to be at risk of developing the disease.  Both parents of an affected animal must be carriers of at least one copy of the mutation.  Animals that have only one copy of the mutation are not at risk of developing the disease but are carrier animals that can pass the mutation on to future generations.

Mutation: Deletion, MIA3 gene (splicing error): c.3822+3_3822+4 del.AT, p.(Val1238_Lys1274 with the skipping of 2 exons), Ch.38.

Medical system: Skeletal, dental, ocular

Breed: Cane Corso

Age of onset of symptoms: by 6 months.

A hereditary syndrome was identified in Cane Corso dogs involving dental and skeletal anomalies as well as retinal degeneration.   Affected dogs were small in size with short, bent legs and had teeth that were brittle, transparent and discolored. Retinal degeneration was progressive, leading to blindness.

Molecular studies identified a splicing error mutation within the MIA3 gene which codes for the MIA3 protein, sometimes called the TANGO1 protein.   This protein is involved in the cellular transport of proteins targeted for secretion into the extracellular space including the collagen proteins.  The collagens are a family of structural extracellular proteins important for proper bone, skin and teeth formation. Disruption of proper collagen secretion via mutations of the MIA3 gene account for the clinical features of DSRA, as seen in humans, mice and now dogs.  A small-scale survey involving 18 affected and 22 unaffected Cane Corso dogs confirmed the causal nature of the MIA3 gene mutation.  Determining the frequency of the mutation for the Cane Corso breed at large awaits further investigation.  DNA tests are now available to enable breeders and veterinarians to identify carrier animals and use selective breeding to eliminate this disease.

Disrupted function of collagen genes due to mutations within the collagen genes themselves are responsible for oculoskeletal dysplasia (OSD) phenotypes described in dogs.  See: OSD1, OSD2.

References:

OMIA link: [2465-9615]

Brown AT, Peak RM, Smithson CW, Bell C. (2024) Dental abnormalities in two dental-skeletal-retinal anomaly-positive Cane Corso dogs: A case series. J Vet Dent 41:409-423.  [pm/38146186]

Mack Wilson J, Bell C, Queck K, Scott K. (2022) A review of dentinogenesis imperfecta and primary dentin disorders in dogs.  J Vet Dent. 39(4):376-390.  [pm/36113440]

Christen M, Booij-Vrieling H, Oksa-Minalto J, et al. (2021) MIA3 Splice Defect in Cane Corso Dogs with Dental-Skeletal-Retinal Anomaly (DSRA). Genes (Basel) 12:1497. [pm/34680893]

Saito K, Chen M, Bard F, et al. (2009) TANGO1 facilitates cargo loading at endoplasmic reticulum exit sites. Cell 136:891-902. [pm/19269366]