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Publication - Dr Nicolas Granger

    A mutation in the Warburg syndrome gene, RAB3GAP1, causes a similar syndrome with polyneuropathy and neuronal vacuolation in Black Russian Terrier dogs

    Citation

    Mhlanga-Mutangadura, T, Johnson, GS, Schnabel, RD, Taylor, JF, Johnson, GC, Katz, ML, Shelton, GD, Lever, TE, Giuliano, E, Granger, N, Shomper, J & O'Brien, DP, 2016, ‘A mutation in the Warburg syndrome gene, RAB3GAP1, causes a similar syndrome with polyneuropathy and neuronal vacuolation in Black Russian Terrier dogs’. Neurobiology of Disease, vol 86., pp. 75-85

    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.

    Full details in the University publications repository