title: A mutation in the Warburg syndrome gene, RAB3GAP1, causes a similar syndrome with polyneuropathy and neuronal vacuolation in Black Russian Terrier dogs.
abstract: An autosomal recessive disease of Black Russian Terriers was previously described as a juvenile-onset, laryngeal paralysis and polyneuropathy similar to Charcot Marie Tooth disease in humans. We found that in addition to an axonal neuropathy, affected dogs exhibit microphthalmia, cataracts, and miotic pupils. On histopathology, affected dogs exhibit a spongiform encephalopathy characterized by accumulations of abnormal, membrane-bound vacuoles of various sizes in neuronal cell bodies, axons and adrenal cells. DNA from an individual dog with this polyneuropathy with ocular abnormalities and neuronal vacuolation (POANV) was used to generate a whole genome sequence which contained a homozygous RAB3GAP1:c.743delC mutation that was absent from 73 control canine whole genome sequences. An additional 12 Black Russian Terriers with POANV were RAB3GAP1:c.743delC homozygotes. DNA samples from 249 Black Russian Terriers with no known signs of POANV were either heterozygotes or homozygous for the reference allele. Mutations in human RAB3GAP1 cause Warburg micro syndrome (WARBM), a severe developmental disorder characterized by abnormalities of the eye, genitals and nervous system including a predominantly axonal peripheral neuropathy. RAB3GAP1 encodes the catalytic subunit of a GTPase activator protein and guanine exchange factor for Rab3 and Rab18 respectively. Rab proteins are involved in membrane trafficking in the endoplasmic reticulum, axonal transport, autophagy and synaptic transmission. The neuronal vacuolation and membranous inclusions and vacuoles in axons seen in this canine disorder likely reflect alterations of these processes. Thus, this canine disease could serve as a model for WARBM and provide insight into its pathogenesis and treatment.
authors.affiliation: Department of Veterinary Pathobiology, University of Missouri, Columbia, USA.
authors.forename: Tendai
authors.initials: T
authors.lastname: Mhlanga-Mutangadura
authors.affiliation: Department of Veterinary Pathobiology, University of Missouri, Columbia, USA.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Johnson
authors.affiliation: Division of Animal Sciences, University of Missouri, Columbia, USA; Informatics Institute, University of Missouri, Columbia, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Schnabel
authors.affiliation: Division of Animal Sciences, University of Missouri, Columbia, USA.
authors.forename: Jeremy F
authors.initials: JF
authors.lastname: Taylor
authors.affiliation: Department of Veterinary Pathobiology, University of Missouri, Columbia, USA.
authors.forename: Gayle C
authors.initials: GC
authors.lastname: Johnson
authors.affiliation: Mason Eye Institute, University of Missouri, Columbia, USA.
authors.forename: Martin L
authors.initials: ML
authors.lastname: Katz
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, USA.
authors.forename: G Diane
authors.initials: GD
authors.lastname: Shelton
authors.affiliation: Department of Otolaryngology, University of Missouri, Columbia, USA.
authors.forename: Teresa E
authors.initials: TE
authors.lastname: Lever
authors.affiliation: Department of Veterinary Medicine & Surgery, University of Missouri, Columbia, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Giuliano
authors.affiliation: School of Veterinary Sciences, University of Bristol, Langford House, Langford, Somerset BS40 5DU, UK.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Granger
authors.affiliation: Department of Veterinary Medicine & Surgery, University of Missouri, Columbia, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Shomper
authors.affiliation: Department of Veterinary Medicine & Surgery, University of Missouri, Columbia, USA. Electronic address: obriend@missouri.edu.
authors.forename: Dennis P
authors.initials: DP
authors.lastname: O'Brien
mesh_terms: D000818:Animals; D002386:Cataract / Q000235:genetics / Q000473:pathology; D002531:Cerebellum / Q000378:metabolism / Q000648:ultrastructure; D003593:Cytoplasm / Q000648:ultrastructure; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D007821:Laryngeal Muscles / Q000648:ultrastructure; D007830:Larynx / Q000473:pathology; D008297:Male; D009154:Mutation; D009474:Neurons / Q000378:metabolism / Q000648:ultrastructure; D010641:Phenotype; D011115:Polyneuropathies / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology / Q000662:veterinary; D058494:Walker-Warburg Syndrome / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology / Q000662:veterinary; D020692:rab3 GTP-Binding Proteins / Q000235:genetics*
chemical_list: D020692:rab3 GTP-Binding Proteins
keywords: Canine; Endoplasmic reticulum; Martsolf syndrome; Membrane trafficking; Rab GTPase; Spongiform encephalopathy; Warburg micro syndrome