CMT 4J: Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and p

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Nature. 2007 Jun 17

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.

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)P(2)), 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)P(2) 5-phosphatase located

in the vacuolar membrane. The abnormal concentration of PtdIns(3,5)P

(2) 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.