RESUMO
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.
Assuntos
Anemia Sideroblástica/genética , Cardiomiopatias/genética , Doenças do Cão/genética , Tirosina-tRNA Ligase/genética , Anemia Sideroblástica/mortalidade , Anemia Sideroblástica/veterinária , Animais , Cardiomiopatias/mortalidade , Cardiomiopatias/veterinária , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Doenças do Cão/mortalidade , Doenças do Cão/patologia , Cães , Genes Recessivos/genética , Ligação Genética , Genoma/genética , Mutação de Sentido Incorreto/genética , LinhagemRESUMO
Sideroblastic anemia is an anemic condition characterized by chronic hypochromic anemia and the presence of large iron deposits in erythroid cells. Seven dogs with sideroblastic anemia were evaluated retrospectively. Historical, clinical, and clinicopathologic findings were reviewed to determine whether the condition was idiopathic or associated with disease conditions or drug or toxin exposure. Associated diseases were identified in 6 affected dogs and included acute hepatitis, pancreatitis, acute hepatitis and pancreatitis, inflammatory disease, glomerulonephritis, and myelofibrosis. None of the dogs had a history of recent exposure to drugs or toxins. One dog had no evidence of associated disease. Regardless of the associated disease condition, sideroblastic anemia was characterized by moderate to severe nonregenerative and frequently hypochromic anemia with prominent dysplastic features in bone marrow that were most prominent in the erythroid series. Survival varied from days to years. Identification of large numbers of siderocytes or sideroblasts in blood or bone marrow is inconsistent with a diagnosis of iron deficiency and should prompt a search for inflammatory disease conditions, including hepatitis, pancreatitis, and glomerulonephritis.
