Categories: Cardiovascular system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 613561 (trait) , 610957 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2020

Cross-species summary: Renamed from 'Cardiomyopathy and juvenile mortality' to 'Cardiomyopathy and juvenile mortality, YARS2-related' [25/05/2024]

Inheritance: Gurtner et al. (2020): "Pedigree analysis suggested a monogenic autosomal recessive inheritance."

Mapping: Gurtner et al. (2020): "Combined linkage and homozygosity mapping assigned the most likely position of a potential genetic defect to 13 genome segments totaling 82 Mb."

Molecular basis: Gurtner et al. (2020): "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." The variant substitutes a negatively charged glutamate with a positively charged lysine on the surface of the tRNA-binding domain of the mitochondrial tyrosyl-tRNA synthetase 2. Protein translation requires aminoacyl-tRNAs to deliver the amino acids that are incorporated into nascent peptide chains. Aminoacylation of tRNAs is catalyzed by a set of aminoacyl-tRNA synthetases, which have highly specific recognition sites for their respective amino acids and the corresponding tRNA molecules. Eukaryotes have two tyrosyl-tRNA synthetases, the cytoplasmic tyrosyl-tRNA synthetase 1 (YARS1) and the mitochondrial tyrosyl-tRNA synthetase 2 (YARS2). A mitochondrial translation defect due to the YARS2:p.Glu352Lys represents a plausible cause for juvenile mortality in Belgian Shepherd dogs (Gurtner et al. 2020).

Clinical features: The clinical phenotype is unspecific and variable. In the study of Gurtner et al. (2020), three affected puppies were studied, which all died at 8 weeks of age. A few days prior to death they showed various clinical signs such as vomiting and dyspnea (n = 2) or lethargy and muscle twitching (n = 1) (Gurtner et al. 2020).

Pathology: Cardiomyocytes of affected puppies were swollen and pale, and the sarcoplasm around the nucleus was dispersed by finely granular material (Gurtner et al. 2020). The authors concluded: "The cause of disease and death were likely due to the degenerative changes in the heart, leading to myocardial failure."

Prevalence: Gurtner et al. (2020): "The carrier frequency was 27.2% in the tested Belgian Shepherd dogs"

Breed: Belgian Shepherd Dog (Dog) (VBO_0200144).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: