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BACKGROUND: Hypertriglyceridemia (HTG) is prevalent in Miniature Schnauzers, predisposing them to life-threatening diseases. Varied responses to management strategies suggest the possibility of multiple subtypes. HYPOTHESIS/OBJECTIVE: To identify and characterize HTG subtypes in Miniature Schnauzers through cluster analysis of lipoprotein profiles. We hypothesize that multiple phenotypes of primary HTG exist in this breed. ANIMALS: Twenty Miniature Schnauzers with normal serum triglyceride concentration (NTG), 25 with primary HTG, and 5 with secondary HTG. METHODS: Cross-sectional study using archived samples. Lipoprotein profiles, generated using continuous lipoprotein density profiling, were clustered with hierarchical cluster analysis. Clinical data (age, sex, body condition score, and dietary fat content) was compared between clusters. RESULTS: Six clusters were identified. Dogs with primary HTG were dispersed among 4 clusters. One cluster showed the highest intensities for triglyceride-rich lipoprotein (TRL) and low-density lipoprotein (LDL) fractions and also included 4 dogs with secondary HTG. Two clusters had moderately high TRL fraction intensities and low-to-intermediate LDL intensities. The fourth cluster had high LDL but variable TRL fraction intensities with equal numbers of NTG and mild HTG dogs. The final 2 clusters comprised only NTG dogs with low TRL intensities and low-to-intermediate LDL intensities. The clusters did not appear to be driven by differences in the clinical data. CONCLUSIONS AND CLINICAL IMPORTANCE: The results of this study support a spectrum of lipoprotein phenotypes within Miniature Schnauzers that cannot be predicted by triglyceride concentration alone. Lipoprotein profiling might be useful to determine if subtypes have different origins, clinical consequences, and response to treatment.

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Miniature Schnauzers are predisposed to primary hypertriglyceridemia (HTG). In this study, we performed whole genome sequencing (WGS) of eight Miniature Schnauzers with primary HTG and screened for risk variants in six HTG candidate genes: LPL, APOC2, APOA5, GPIHBP1, LMF1, and APOE. Variants were filtered to identify those present in ≥2 Miniature Schnauzers with primary HTG and uncommon (<10% allele frequency) in a WGS variant database including 613 dogs from 61 other breeds. Three variants passed filtering: an APOE TATA box deletion, an LMF1 intronic SNP, and a GPIHBP1 missense variant. The APOE and GPIHBP1 variants were genotyped in a cohort of 108 Miniature Schnauzers, including 68 with primary HTG and 40 controls. A multivariable regression model, including age and sex, did not identify an effect of APOE (estimate = 0.18, std. error = 0.14; p = 0.20) or GPIHBP1 genotypes (estimate = -0.26, std. error = 0.42; p = 0.54) on triglyceride concentration. In conclusion, we did not identify a monogenic cause for primary HTG in Miniature Schnauzers in the six genes evaluated. However, if HTG in Miniature Schnauzers is a complex disease resulting from the cumulative effects of multiple variants and environment, the identified variants cannot be ruled out as contributing factors.

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Hereditary xanthinuria is a rare autosomal recessive disease caused by missense and loss of function variants in the xanthine dehydrogenase (XDH) or molybdenum cofactor sulfurase (MOCOS) genes. The aim of this study was to uncover variants underlying risk for xanthinuria in dogs. Affected dogs included two Manchester Terriers, three Cavalier King Charles Spaniels, an English Cocker Spaniel, a Dachshund, and a mixed-breed dog. Four putative causal variants were discovered: an XDH c.654G > A splice site variant that results in skipping of exon 8 (mixed-breed dog), a MOCOS c.232G > T splice site variant that results in skipping of exon 2 (Manchester Terriers), a MOCOS p.Leu46Pro missense variant (Dachshund), and a MOCOS p.Ala128Glyfs*30 frameshift variant that results in a premature stop codon (Cavalier King Charles Spaniels and English Cocker Spaniel). The two splice site variants suggest that the regions skipped are critical to the respective enzyme function, though protein misfolding is an alternative theory for loss of function. The MOCOS p.Leu46Pro variant has not been previously reported in human or other animal cases and provides novel data supporting this residue as critical to MOCOS function. All variants were present in the homozygous state in affected dogs, indicating an autosomal recessive mode of inheritance. Allele frequencies of these variants in breed-specific populations ranged from 0 to 0.18. In conclusion, multiple diverse variants appear to be responsible for hereditary xanthinuria in dogs.

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It has been hypothesized that idiopathic hypertriglyceridemia in Miniature Schnauzers is hereditary, but the gene responsible has yet to be identified. The objective of this study was to determine if there were coding variants in the apolipoprotein C2 (APOC2) gene in Miniature Schnauzers with idiopathic hypertriglyceridemia. Blood samples from 12 Miniature Schnauzers with idiopathic hypertriglyceridemia were analyzed. Genomic DNA was extracted from whole blood, and the three coding exons of APOC2 were amplified by PCR. The PCR amplicons were sequenced and analyzed for variants relative to the canine reference genome (CanFam3.1 assembly). A second objective was to determine the extent of variation in coding exons of APOC2 in a large and diverse canine population using the Dog Biomedical Variant Database Consortium variant catalog, comprised of whole genome sequencing variant calls from 582 dogs of 126 breeds and eight wolves. There were no variants detected in the coding exons of APOC2 for any of the 12 Miniature Schnauzers with idiopathic hypertriglyceridemia. Variants in the coding exons of APOC2 were also rare in the Dog Biomedical Variant Database Consortium variant catalog; a single synonymous variant was identified in a heterozygous state in a Tibetan Mastiff. Thus, we concluded that coding variants in APOC2 are unlikely to be a major cause of idiopathic hypertriglyceridemia in North American Miniature Schnauzers and furthermore, that such coding variants are rare in the canine population.

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A 2-year-old mixed breed goat was presented for a 1-day history of anorexia and 1 week of weight loss. Serum biochemistry disclosed severe azotemia. Abdominal ultrasound examination showed decreased renal corticomedullary distinction, poor visualization of the renal pelves, and dilated ureters. On necropsy, the kidneys were small, the pelves were dilated, and the medulla was partially effaced by variably sized yellow nephroliths. Histologically, cortical and medullary tubules were distended by yellow-brown, multilayered crystals. Stone composition was 100% xanthine. Exonic sequencing of xanthine dehydrogenase (XDH) and molybdenum cofactor sulfurase (MOCOS) identified 2 putative pathogenic variants: a heterozygous XDH p.Leu128Pro variant and a homozygous MOCOS p.Asp303Gly variant. Variant frequencies were determined in 7 herd mates, 12 goats undergoing necropsy, and 443 goats from genome databases. The XDH variant was not present in any of these 462 goats. The MOCOS variant allele frequency was 0.03 overall, with 3 homozygotes detected. Hereditary xanthinuria is a recessive disorder in other species, but the XDH variant could be causal if the case goat is a compound heterozygote harboring a second variant in a regulatory region not analyzed or if the combination of the XDH and MOCOS variants together abolish XDH activity. Alternatively, the MOCOS variant alone could be causal despite the presence of other homozygotes, because hereditary xanthinuria in humans often is asymptomatic. Ours is the first report describing the clinical presentation and pathology associated with xanthine urolithiasis in a goat. The data support hereditary xanthinuria, but functional studies are needed to conclusively determine the causal variant(s).

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