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.
Highlights
Increased puppy loss is an animal welfare concern associated with emotional and financial burdens to dog breeders
Various infections may result in puppy loss [5,6] and bacterial infections in puppies are the most common infectious cause for diseases and overall the second most important cause of mortality in neonatal dogs [7]
We identified the YARS2:c.1054G>A variant and a mitochondrial translation defect as the potential cause for juvenile mortality in Belgian Shepherd dogs
Summary
Increased puppy loss is an animal welfare concern associated with emotional and financial burdens to dog breeders. The rate of stillbirths and neonatal death within the first weeks of life is known to be high [1,2]. During the first days of life, the death rate in puppies is highest [3] as there are various predisposing factors that can lead to life-threatening illnesses and subsequent death. Non-infectious causes, such as prolonged delivery and dystocia, are the most common factors leading to early death in new-born puppies [3]. Structural or functional congenital malformations as further non-infectious causes may lead to early puppy death or be an indication for euthanasia [4]. The sudden death of puppies after several weeks of normal development is less common as they have survived potentially threatening immunological and nutritional issues associated with birth [1,2]
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