Dataset Information

A deletion of IDUA exon 10 in a family of Golden Retriever dogs with an attenuated form of mucopolysaccharidosis type I.

ABSTRACT: BACKGROUND:Mucopolysaccharidosis type I (MPS-I) is a lysosomal storage disorder caused by a deficiency of the enzyme ?-l-iduronidase, leading to accumulation of undegraded dermatan and heparan sulfates in the cells and secondary multiorgan dysfunction. In humans, depending upon the nature of the underlying mutation(s) in the IDUA gene, the condition presents with a spectrum of clinical severity. OBJECTIVES:To characterize the clinical and biochemical phenotypes, and the genotype of a family of Golden Retriever dogs. ANIMALS:Two affected siblings and 11 related dogs. METHODS:Family study. Urine metabolic screening and leucocyte lysosomal enzyme activity assays were performed for biochemical characterization. Whole genome sequencing was used to identify the causal mutation. RESULTS:The clinical signs shown by the proband resemble the human attenuated form of the disease, with a dysmorphic appearance, musculoskeletal, ocular and cardiac defects, and survival to adulthood. Urinary metabolic studies identified high levels of dermatan sulfate, heparan sulfate, and heparin. Lysosomal enzyme activities demonstrated deficiency in ?-l-iduronidase activity in leucocytes. Genome sequencing revealed a novel homozygous deletion of 287?bp resulting in full deletion of exon 10 of the IDUA gene (NC_006585.3(NM_001313883.1):c.1400-76_1521+89del). Treatment with pentosan polyphosphate improved the clinical signs until euthanasia at 4.5?years. CONCLUSION AND CLINICAL IMPORTANCE:Analysis of the genotype/phenotype correlation in this dog family suggests that dogs with MPS-I could have a less severe phenotype than humans, even in the presence of severe mutations. Treatment with pentosan polyphosphate should be considered in dogs with MPS-I.

SUBMITTER: Faller KME

PROVIDER: S-EPMC7517864 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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A deletion of IDUA exon 10 in a family of Golden Retriever dogs with an attenuated form of mucopolysaccharidosis type I.

Faller Kiterie M E KME Ridyard Alison E AE Gutierrez-Quintana Rodrigo R Rupp Angie A Kun-Rodrigues Celia C Orme Tatiana T Tylee Karen L KL Church Heather J HJ Guerreiro Rita R Bras Jose J

Journal of veterinary internal medicine 20200812 5

<h4>Background</h4>Mucopolysaccharidosis type I (MPS-I) is a lysosomal storage disorder caused by a deficiency of the enzyme α-l-iduronidase, leading to accumulation of undegraded dermatan and heparan sulfates in the cells and secondary multiorgan dysfunction. In humans, depending upon the nature of the underlying mutation(s) in the IDUA gene, the condition presents with a spectrum of clinical severity.<h4>Objectives</h4>To characterize the clinical and biochemical phenotypes, and the genotype o ...[more]

PMID: 32785987

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Project description:Background:Dogs have human-directed social skills that allow them to communicate and cooperate with humans. We have previously identified two loci on chromosome 26 associated with human contact-seeking behaviors during an unsolvable problem task in laboratory beagles (Persson et al., 2016). The aim of the present study was to verify the single nucleotide polymorphisms (SNPs) in additional dog breeds. We also studied how the allele frequencies have changed during domestication and recent selection. Methods:Dogs of two breeds, 61 golden retrievers and 100 Labrador retrievers, were phenotyped and genotyped, and 19 wolves were genotyped. The Labrador retrievers were divided into common and field type by pedigree data to make it possible to study the effects of recent selection. All dogs were tested in an unsolvable problem task where human-directed social behaviors were scored. DNA from dogs (buccal swabs) and wolves (blood or brain tissue) was analyzed for genotype on two of the previously identified SNP markers, BICF2G630798942 (SNP1) and BICF2S23712114 (SNP2), by pyrosequencing. Results:There was genetic variation for SNP1 in both dog breeds whereas the wolves were fixed for this polymorphism, and for SNP2 there was variation in both dogs and wolves. For both SNPs, Labrador retriever types differed significantly in allele frequencies. We found associations between SNPs and human-directed social behavior in both dog breeds. In golden retrievers, SNP1 was associated with physical contact variables, for example, with the duration of physical contact with the owner (F 2,56 = 4.389, p = 0.017). SNP2 was associated with several behavioral variables in both breeds, among others owner gazing frequency in both golden retrievers (F 2,55 = 6.330, p = 0.003) and Labradors (F 1,93 = 5.209, p = 0.025). Discussion:Our results verify the association between the previously identified SNPs and human-directed social behavior scored in an unsolvable problem task. Differences in allele frequencies suggest that these loci have been affected by selection. The results indicate that these genomic regions are involved in human-directed social behavior in not only beagles but in other dog breeds as well. We hypothesize that they may have been important during dog domestication.

Dataset Information

A deletion of IDUA exon 10 in a family of Golden Retriever dogs with an attenuated form of mucopolysaccharidosis type I.

Publications

A deletion of IDUA exon 10 in a family of Golden Retriever dogs with an attenuated form of mucopolysaccharidosis type I.

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