Dataset Information

Hereditary sensory and autonomic neuropathy in a family of mixed breed dogs associated with a novel RETREG1 variant.

ABSTRACT:

Background

Hereditary sensory and autonomic neuropathies (HSANs) are a group of genetic disorders affecting the peripheral nervous system. Two different associated variants have been identified in dogs: 1 in Border Collies and 1 in Spaniels and Pointers.

Objectives

Clinically and genetically characterize HSAN in a family of mixed breed dogs.

Animals

Five 7-month-old mixed breed dogs from 2 related litters were presented for evaluation of a 2-month history of acral mutilation and progressive pelvic limb gait abnormalities.

Methods

Complete physical, neurological, electrodiagnostic, and histopathological evaluations were performed. Whole genome sequencing of 2 affected dogs (1 from each litter) was used to identify variants that were homozygous or heterozygous in both cases, but wild type in 217 control genomes of 100 breeds. Immunohistochemistry was used to assess protein expression.

Results

Complete physical, neurological, electrodiagnostic, and histopathological evaluations confirmed a disorder affecting sensory and autonomic nerves. Whole genome sequencing identified a missense variant in the RETREG1 (reticulophagy regulator 1) gene (c.656C > T, p.P219L). All affected dogs were homozygous for the variant, which was not detected in 1193 dogs from different breeds. Immunohistochemistry showed no expression of RETREG1 in the cerebellum of affected dogs. One of the affected dogs lived for 5 years and showed gradual progression of the clinical signs.

Conclusions and clinical importance

We confirmed the diagnosis of HSAN in a family of mixed breed dogs and identified a novel and possibly pathogenic RETREG1 variant. Affected dogs experienced gradual deterioration over several years.

SUBMITTER: Gutierrez-Quintana R

PROVIDER: S-EPMC8478055 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Publications

Hereditary sensory and autonomic neuropathy in a family of mixed breed dogs associated with a novel RETREG1 variant.

Gutierrez-Quintana Rodrigo R Mellersh Cathryn C Wessmann Annette A Ortega Maria M Penderis Jacques J Sharpe Samuel S Freeman Eleanor E Stevenson Lynn L Burmeister Louise L

Journal of veterinary internal medicine 20210813 5

<h4>Background</h4>Hereditary sensory and autonomic neuropathies (HSANs) are a group of genetic disorders affecting the peripheral nervous system. Two different associated variants have been identified in dogs: 1 in Border Collies and 1 in Spaniels and Pointers.<h4>Objectives</h4>Clinically and genetically characterize HSAN in a family of mixed breed dogs.<h4>Animals</h4>Five 7-month-old mixed breed dogs from 2 related litters were presented for evaluation of a 2-month history of acral mutilatio ...[more]

PMID: 34387380

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Project description:DNA methyltransferase 1 (DNMT1) is essential for DNA methylation, gene regulation and chromatin stability. We previously discovered DNMT1 mutations cause hereditary sensory and autonomic neuropathy type 1 with dementia and hearing loss (HSAN1E; OMIM 614116). HSAN1E is the first adult-onset neurodegenerative disorder caused by a defect in a methyltransferase gene. HSAN1E patients appear clinically normal until young adulthood, then begin developing the characteristic symptoms involving central and peripheral nervous systems. Some HSAN1E patients also develop narcolepsy and it has recently been suggested that HSAN1E is allelic to autosomal dominant cerebellar ataxia, deafness, with narcolepsy (ADCA-DN; OMIM 604121), which is also caused by mutations in DNMT1. A hotspot mutation Y495C within the targeting sequence domain of DNMT1 has been identified among HSAN1E patients. The mutant DNMT1 protein shows premature degradation and reduced DNA methyltransferase activity. Herein, we investigate genome-wide DNA methylation at single-base resolution through whole-genome bisulfite sequencing of germline DNA in 3 pairs of HSAN1E patients and their gender- and age-matched siblings. Over 1 billion 75-bp single-end reads were generated for each sample. In the 3 affected siblings, overall methylation loss was consistently found in all chromosomes with X and 18 being most affected. Paired sample analysis identified 564,218 differentially methylated CpG sites (DMCs; P<0.05), of which 300 134 were intergenic and 264 084 genic CpGs. Hypomethylation was predominant in both genic and intergenic regions, including promoters, exons, most CpG islands, L1, L2, Alu, and satellite repeats and simple repeat sequences. In some CpG islands, hypermethylated CpGs outnumbered hypomethylated CpGs. In 201 imprinted genes, there were more DMCs than in non-imprinted genes and most were hypomethylated. Differentially methylated region (DMR) analysis identified 5649 hypomethylated and 1872 hypermethylated regions. Importantly, pathway analysis revealed 1693 genes associated with the identified DMRs were highly associated in diverse neurological disorders and NAD+/NADH metabolism pathways is implicated in the pathogenesis. Our results provide novel insights into the epigenetic mechanism of neurodegeneration arising from a hotspot DNMT1 mutation and reveal pathways potentially important in a broad category of neurological and psychological disorders.

Dataset Information

Hereditary sensory and autonomic neuropathy in a family of mixed breed dogs associated with a novel RETREG1 variant.

Background

Objectives

Animals

Methods

Results

Conclusions and clinical importance

Publications

Hereditary sensory and autonomic neuropathy in a family of mixed breed dogs associated with a novel RETREG1 variant.

Similar Datasets

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