(C44) A Novel Nonsynonymous Gene Variant in IDUA in Basset Hounds with Mucopolysaccharidosis Type 1

A Novel Nonsynonymous Gene Variant in IDUA in Basset Hounds with Mucopolysaccharidosis Type 1
 Elizabeth A. Martin, Dennis O’Brien, Gary S. Johnson, Gayle C. Johnson, Stacey B. Leach.
Abstract: 

Background: Mucopolysaccharidoses (MPS) are a collection of heritable lysosomal storage disorders that result in multi-systemic dysfunction including cardiac disease. The most severe form (MPS1 or Hurler’s syndrome) is due to deficiencies in the alpha-L-iduronidase enzyme.
Hypothesis/

Objectives: To describe the clinical cardiac features in a family of Basset hounds and to identify the causal mutation.
Animals: Three related Basset hounds with suspected MPS and DNA samples from 740 individual Basset hounds.

Methods: Echocardiography, electrocardiography, and post-mortem evaluations were performed in the clinically affected dogs. Whole genome sequencing was performed from a related dog with compatible clinical signs and a positive toluidine urine spot test for MPS. DNA samples from both related and unrelated Basset hounds were genotyped for the likely causal sequence variant with an allelic discrimination assay



Results: Affected dogs had varying degrees of mitral, tricuspid, and aortic valvular thickening and regurgitation as well as aortic root dilation. No arrhythmias or conduction disturbances were noted. Histopathology confirmed excessive glycosaminoglycan accumulation within the cardiac valves. Whole genome sequencing revealed a rare, but likely causal homozygous glycine-to-serine missense mutation in IDUA. To date, genotyping has revealed 13 DNA samples homozygous for the variant allele (including the clinically affected dogs), 50 were heterozygous, and 677 tested homozygous for the reference allele. The variant allele frequency was 5.6% for the genotyped cohort.

Conclusions and Clinical Importance: A novel IDUA variant is associated with the development of classical cardiac signs of MPS1 in Basset hounds and genetic testing may help guide breeding decisions.