Two mixed breed dogs with sensory neuropathy are homozygous for an inversion disrupting<i>FAM134B</i>previously identified in Border Collies

Amengual-Batle, Pablo; Rusbridge, Clare; José-López, Roberto; Golini, Lorenzo; Shelton, G. Diane; Mellersh, Cathryn S.; Gutierrez‐Quintana, Rodrigo

doi:10.1111/jvim.15312

Cited by 8 publications

(15 citation statements)

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“…A genome‐wide association study revealed the disruption of the FAM134B gene due to an inversion in Border Collies with neurological diseases (Forman et al, 2016). Amengual‐Batle et al (2018) also reported homozygous mutations of FAM134B in two unrelated 8‐month‐old male mixed‐breed dogs who showed the same symptoms as the border collie with sensory neuropathy described by Forman et al (2016).…”

Section: Role Of Fam134b In Organelle Membrane Morphogenesis and Diseasesmentioning

confidence: 69%

Roles of FAM134B in diseases from the perspectives of organelle membrane morphogenesis and cellular homeostasis

Zhu

Wang

2021

Journal Cellular Physiology

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Family with sequence similarity 134 member B (FAM134B)/RETREG1/JK1 is a novel gene with recently reported roles in various diseases. Understanding the function and mechanism of action of FAM134B is necessary to develop disease therapies. Notably, emerging data are clarifying the molecular mechanisms of FAM134B function in organelle membrane morphogenesis and the regulation of signaling pathways, such as the Wnt and AKT signaling pathways. In addition, transcription factors, RNA N6‐methyladenosine‐mediated epigenetic regulation, microRNA, and small molecules are involved in the regulation of FAM134B expression. This review comprehensively considers recent studies on the role of FAM134B and its potential mechanisms in neurodegenerative diseases, obesity, viral diseases, cancer, and other diseases. The functions of FAM134B in maintaining cell homeostasis by regulating Golgi morphology, endoplasmic reticulum autophagy, and mitophagy are also highlighted, which may be the underlying mechanism of FAM134B gene mutation‐induced diseases. Moreover, the molecular mechanisms of the FAM134B function during numerous biological processes are discussed. This review provides novel insights into the functions and mechanisms of FAM134B in various diseases, which will inform the development of effective drugs to treat diseases.

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Section: Role Of Fam134b In Organelle Membrane Morphogenesis and Diseasesmentioning

confidence: 69%

Roles of FAM134B in diseases from the perspectives of organelle membrane morphogenesis and cellular homeostasis

Zhu

Wang

2021

Journal Cellular Physiology

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“…This finding is consistent with a polymorphic, but benign, microsatellite marker, and this WNK1 variant therefore was excluded from further examination. RETREG1 was reported previously to cause sensory neuropathy in dogs 5,9 and humans 31 . The variant in RETREG1 therefore remains the strongest candidate variant and was retained for further investigation.…”

Section: Resultsmentioning

confidence: 90%

“…Although HSANs have been reported in different dog breeds including Border Collie, 5‐8 Border Collie cross, 9 Long‐haired Dachshund, 10,11 Miniature Pincher, 12 Jack Russell Terrier, 13 Pointer, 14‐17 English Springer Spaniel, 17 French Spaniel, 17,18 and Fox Terrier, 4 only 2 causal variants have been identified to date. The first is an inversion disrupting RETREG1 ( reticulophagy regulator 1 ), encoding a Golgi protein, in Border Collies and Border Collie crosses (Online Mendelian Inheritance in Animals [OMIA] 002032‐9615) 5,9 . The second is a point variant in a lincRNA upstream of the GDNF gene encoding glial cell‐derived neurotrophic factor in the Pointer, English Springer Spaniel, and French Spaniel (OMIA 001514‐9615) 17 …”

Section: Introductionmentioning

confidence: 99%

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

Gutierrez‐Quintana

Mellersh

Wessmann

et al. 2021

Veterinary Internal Medicne

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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.

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“…Older neuropathies, such as the well-known inherited sensory and autonomic in the Border Collie first described in 1987 (Wheeler, 1987), have also benefited from genetic advances. In 2016 one causal genetic variant of FAM134B , which encodes a cis -Golgi protein found in sensory and autonomic ganglion neurons, has been discovered (Forman et al, 2016) and two-years later, this mutation was also described in two mixed breed dogs (Amengual-Batle et al, 2018). In four other breeds, the German short-haired Pointer, the English Pointer, the English Springer Spaniel and the French Spaniel, some known since 1964, a similar inherited sensory and autonomic exist and found to be linked to a genetic variation of the long-non-coding RNA located upstream of the Glial cell-Derived Neurotrophic Factor gene, coding for a neurotrophic factor involved in neuronal development and adult neuronal survival (Plassais et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Charcot-Marie-Tooth type 4B2 demyelinating neuropathy in miniature Schnauzer dogs caused by a novel splicingSBF2 (MTMR13)genetic variant: a new spontaneous clinical model

Granger

Feliu‐Pascual²,

Spicer

et al. 2019

PeerJ

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BackgroundCharcot-Marie-Tooth (CMT) disease is the most common neuromuscular disorder in humans affecting 40 out of 100,000 individuals. In 2008, we described the clinical, electrophysiological and pathological findings of a demyelinating motor and sensory neuropathy in Miniature Schnauzer dogs, with a suspected autosomal recessive mode of inheritance based on pedigree analysis. The discovery of additional cases has followed this work and led to a genome-wide association mapping approach to search for the underlying genetic cause of the disease.MethodsFor genome wide association screening, genomic DNA samples from affected and unaffected dogs were genotyped using the Illumina CanineHD SNP genotyping array. SBF2 and its variant were sequenced using primers and PCRs. RNA was extracted from muscle of an unaffected and an affected dog and RT-PCR performed. Immunohistochemistry for myelin basic protein was performed on peripheral nerve section specimens.ResultsThe genome-wide association study gave an indicative signal on canine chromosome 21. Although the signal was not of genome-wide significance due to the small number of cases, the SBF2 (also known as MTMR13) gene within the region of shared case homozygosity was a strong positional candidate, as 22 genetic variants in the gene have been associated with demyelinating forms of Charcot-Marie-Tooth disease in humans. Sequencing of SBF2 in cases revealed a splice donor site genetic variant, resulting in cryptic splicing and predicted early termination of the protein based on RNA sequencing results.ConclusionsThis study reports the first genetic variant in Miniature Schnauzer dogs responsible for the occurrence of a demyelinating peripheral neuropathy with abnormally folded myelin. This discovery establishes a genotype/phenotype correlation in affected Miniature Schnauzers that can be used for the diagnosis of these dogs. It further supports the dog as a natural model of a human disease; in this instance, Charcot-Marie-Tooth disease. It opens avenues to search the biological mechanisms responsible for the disease and to test new therapies in a non-rodent large animal model. In particular, recent gene editing methods that led to the restoration of dystrophin expression in a canine model of muscular dystrophy could be applied to other canine models such as this before translation to humans.

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Two mixed breed dogs with sensory neuropathy are homozygous for an inversion disruptingFAM134Bpreviously identified in Border Collies

Cited by 8 publications

References 29 publications

Roles of FAM134B in diseases from the perspectives of organelle membrane morphogenesis and cellular homeostasis

Roles of FAM134B in diseases from the perspectives of organelle membrane morphogenesis and cellular homeostasis

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

Charcot-Marie-Tooth type 4B2 demyelinating neuropathy in miniature Schnauzer dogs caused by a novel splicingSBF2 (MTMR13)genetic variant: a new spontaneous clinical model

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