Canine Multiple System Degeneration Associated with Sequence Variants in SERAC1.

Area of Science:

• Genetics
• Canine Diseases
• Neurology

Background:

• Canine multiple system degeneration (CMSD) is an inherited, early-onset movement disorder affecting specific dog breeds.
• Pathologic findings include degeneration in the cerebellum, caudate nucleus, and substantia nigra.
• Previous research localized the causative gene to a 15 MB region on canine chromosome 1.

Purpose of the Study:

• To identify the genetic variants responsible for canine multiple system degeneration (CMSD).
• To confirm the inheritance pattern and role of the SERAC1 gene in CMSD.
• To establish the utility of canine CMSD as a model for human SERAC1-deficiency disorders.

Main Methods:

• Whole-genome sequencing of affected dogs from two breeds (Kerry Blue Terrier, Chinese Crested).
• Bioinformatic analysis to identify homozygous variants within the canine chromosome 1 linkage region.
• RT-PCR to confirm splice site effects and large-scale genotyping for genotype-phenotype correlation.

Main Results:

• Identified a nonsense SERAC1 variant in affected Kerry Blue Terriers.
• Identified a splice site deletion in SERAC1 exon 4 in affected Chinese Crested dogs, leading to exon skipping.
• Demonstrated complete genotype-phenotype concordance in extensive breed cohorts and crossbred offspring, confirming recessive inheritance.

Conclusions:

• Specific mutations in the SERAC1 gene cause canine multiple system degeneration (CMSD).
• CMSD exhibits autosomal recessive inheritance, confirmed by breed-specific and compound heterozygous genotypes.
• Canine CMSD serves as a valuable genetic model for studying human SERAC1-deficiency disorders and potential therapies.