MIA3 Splice Defect in Cane Corso Dogs with Dental-Skeletal-Retinal Anomaly (DSRA)

Abstract

We investigated a hereditary syndrome in Cane Corso dogs. Affected dogs developed dental-skeletal-retinal anomaly (DSRA), clinically characterized by brittle, discolored, translucent teeth, disproportionate growth and progressive retinal degeneration resulting in vision loss. Combined linkage and homozygosity mapping delineated a 5.8 Mb critical interval. The comparison of whole genome sequence data of an affected dog to 789 control genomes revealed a private homozygous splice region variant in the critical interval. It affected the MIA3 gene encoding the MIA SH3 domain ER export factor 3, which has an essential role in the export of collagen and other secreted proteins. The identified variant, XM_005640835.3:c.3822+3_3822+4del, leads to skipping of two exons from the wild type transcript, XM_005640835.3:r.3712_3822del. Genotypes at the variant were consistent with monogenic autosomal recessive mode of inheritance in a complete family and showed perfect genotype-phenotype association in 18 affected and 22 unaffected Cane Corso dogs. MIA3 variants had previously been shown to cause related phenotypes in humans and mice. Our data in dogs together with the existing functional knowledge of MIA3 variants in other mammalian species suggest the MIA3 splice defect and a near complete loss of gene function as causative molecular pathomechanism for the DSRA phenotype in the investigated dogs.

TANGO1 Dances to Export of Procollagen from the Endoplasmic Reticulum

“…Intriguingly, a new syndrome was reported in Cane Corso dogs with hereditary dental pathology that demonstrated a homozygote splice mutation that caused exon skipping in the TANGO1 gene. The authors propose that there was some residual TANGO1 protein activity that allowed for the export of some collagen molecules and therefore the pathology exhibited in the canines was not as severe as that seen in complete knockout animals [ 86 ].…”

Special Issue: “Canine Genetics 2”

“…A new late-onset progressive retinal atrophy (PRA) in Shetland Sheepdogs that is associated with an upturned nose and coat and tooth defects was phenotypically characterized and a variant in BBS2 unraveled as the likely sole causal variant [17]. Another syndrome in Cane Corso dogs, termed the dental-skeletal-retinal anomaly, was phenotypically characterized and a causal variant in MIA3 was identified that is hypothesized to cause a defect in cellular export in the post-translational maturation of various collagens [18]. A new PRKG2-associated skeletal dysplasia leading to pronounced disproportionate dwarfism is reported in Dogo Argentino dogs [19].…”

The First Confirmed Case of Dental-Skeletal- Retinal-Anomaly (DSRA) in the Cane Corso Italiano Dog Breed in the Czech Republic

“…Dental-Skeletal-Retinal Anomaly (DSRA) is a hereditary syndrome in the Cane Corso Italiano dogs which was described in 2021 by Christen et al [5]. DSRA is clinically characterized by brittle, discoloured, translucent teeth, disproportionate growth and progressive retinal degeneration resulting in vision loss.…”

“…DSRA is an autosomal recessively inherited disease. The molecular genetic cause is a mutation in the MIA3 gene which causes erroneous splicing of RNA encoded by this gene [5].…”