Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and CMT4J

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Mutation of FIG4 causes neurodegeneration in the pale tremor mouse

and patients with CMT4J.

Chow CY, Zhang Y, Dowling JJ, Jin N, ka M, Shiga K, Szigeti K,

Shy ME, Li J, Zhang X, Lupski JR, Weisman LS, Meisler MH.

Department of Human Genetics, University of Michigan, Ann Arbor,

Michigan 48109, USA.

Membrane-bound phosphoinositides are signalling molecules that have

a key role in vesicle trafficking in eukaryotic cells. Proteins that

bind specific phosphoinositides mediate interactions between

membrane-bounded compartments whose identity is partially encoded by

cytoplasmic phospholipid tags. Little is known about the

localization and regulation of mammalian phosphatidylinositol-3,5-

bisphosphate (PtdIns(3,5)P2), a phospholipid present in small

quantities that regulates membrane trafficking in the endosome-

lysosome axis in yeast. Here we describe a multi-organ disorder with

neuronal degeneration in the central nervous system, peripheral

neuronopathy and diluted pigmentation in the 'pale tremor' mouse.

Positional cloning identified insertion of ETn2beta (early

transposon 2beta) into intron 18 of Fig4 (A530089I17Rik), the

homologue of a yeast SAC (suppressor of actin) domain PtdIns(3,5)P2

5-phosphatase located in the vacuolar membrane. The abnormal

concentration of PtdIns(3,5)P2 in cultured fibroblasts from pale

tremor mice demonstrates the conserved biochemical function of

mammalian Fig4. The cytoplasm of fibroblasts from pale tremor mice

is filled with large vacuoles that are immunoreactive for LAMP-2

(lysosomal-associated membrane protein 2), consistent with

dysfunction of the late endosome-lysosome axis. Neonatal

neurodegeneration in sensory and autonomic ganglia is followed by

loss of neurons from layers four and five of the cortex, deep

cerebellar nuclei and other localized brain regions. The sciatic

nerve exhibits reduced numbers of large-diameter myelinated axons,

slowed nerve conduction velocity and reduced amplitude of compound

muscle action potentials. We identified pathogenic mutations of

human FIG4 (KIAA0274) on chromosome 6q21 in four unrelated patients

with hereditary motor and sensory neuropathy.

This novel form of autosomal recessive Charcot-Marie-Tooth disorder

is designated CMT4J.