YARS2 Missense Variant in Belgian Shepherd Dogs with Cardiomyopathy and Juvenile Mortality

Abstract

Dog puppy loss by the age of six to eight weeks after normal development is relatively uncommon. Necropsy findings in two spontaneously deceased Belgian Shepherd puppies indicated an abnormal accumulation of material in several organs. A third deceased puppy exhibited mild signs of an inflammation in the central nervous system and an enteritis. The puppies were closely related, raising the suspicion of a genetic cause. Pedigree analysis suggested a monogenic autosomal recessive inheritance. Combined linkage and homozygosity mapping assigned the most likely position of a potential genetic defect to 13 genome segments totaling 82 Mb. The genome of an affected puppy was sequenced and compared to 645 control genomes. Three private protein changing variants were found in the linked and homozygous regions. Targeted genotyping in 96 Belgian Shepherd dogs excluded two of these variants. The remaining variant, YARS2:1054G>A or p.Glu352Lys, was perfectly associated with the phenotype in a cohort of 474 Belgian Shepherd dogs. YARS2 encodes the mitochondrial tyrosyl-tRNA synthetase 2 and the predicted amino acid change replaces a negatively charged and evolutionary conserved glutamate at the surface of the tRNA binding domain of YARS2 with a positively charged lysine. Human patients with loss-of-function variants in YARS2 suffer from myopathy, lactic acidosis, and sideroblastic anemia 2, a disease with clinical similarities to the phenotype of the studied dogs. The carrier frequency was 27.2% in the tested Belgian Shepherd dogs. Our data suggest YARS2:1054G>A as the candidate causative variant for the observed juvenile mortality.

Deletion of the SELENOP gene leads to CNS atrophy with cerebellar ataxia in dogs

“…The clinically similar SDCA2 in Belgian Shepherd dogs is due to a SINE insertion into ATP1B2 encoding the beta 2 subunit of the Na + /K + transporting ATPase (OMIA 002110–9615) [ 10 ]. Finally, we recently identified a variant in YARS2 encoding the mitochondrial tyrosyl-tRNA synthetase as candidate causative variant for cardiomyopathy and juvenile mortality (CJM, OMIA 002256–9615) [ 11 ]. While CJM is not primarily a neurologic disease, it is characterized by a highly variable clinical phenotype that may also include gait abnormalities.…”

Targeting mitochondrial tyrosyl-tRNA synthetase YARS2 suppresses colorectal cancer progression

“…YARS2, which is encoded by the nuclear genome and functions in mitochondria, catalyzes the binding of tyrosine to the cognate mitochondrial tRNAs. 24 According to Pubmed and the Human Genome Mutation Database, pathogenic YARS2 mutations have been linked to myopathy with lactic acidosis and sideroblastic anemia type 2 (MLASA2), 27 Cardiomyopathy, 28 and Sideroblastic anemia with myopathy. 29 In these studies, the patients all carried pathogenic mutations which leads to abnormal mitochondrial function in various tissues, especially skeletal muscles, neurons, etc., indicating that stable expression of YARS2 is essential for cell function and tissue development.…”

Identification of Genetic Risk Factors for Monogenic and Complex Canine Diseases

“…However, separate linkage analyses for each of the litters pointed to different chromosomes. So far, four disease-causing variants leading to identical or at least similar clinical phenotypes have been identified in KCNJ10, ATP1B2, YARS2, and SELENOP (77,(102)(103)(104). Similar to the first example, additional unknown disease-causing variants may exist, as the four known variants still do not explain all known cases of Belgian shepherd dogs with early-onset ataxia (104).…”