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

Abstract

Membrane-bound phosphoinositides are signalling molecules that have a key role in vesicle trafficking in eukaryotic cells 1 . 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 2 . 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 ETn2β (early transposon 2β) 3 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 endosomelysosome 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

Charcot Marie Tooth disease type 4J with complex central nervous system features

“…Recessive mutations (usually compound heterozygous mutations) in FIG4 have caused three distinct clinical phenotypes, CMT4J,7 Yunis‐Varon syndrome,8 and familial epilepsy with polymicrogyria 9. Both Yunis‐Varon syndrome and familial epilepsy with polymicrogyria syndrome are early onset diseases with severely abnormal CNS development and pathology.…”

Assembly of a Fab1 Phosphoinositide Kinase Signaling Complex Requires the Fig4 Phosphoinositide Phosphatase

“…However, in previous studies of the PIKfyve complex, the authors did not elaborate on the role of hVac14 and hSac3 (Fig4 orthologue) in the formation and stability of the PIKfyve complex nor did they explore whether hSac3 positively regulates PtdIns(3,5)P 2 synthesis, as is the case for Fig4. Strikingly, knockout mice for mFig4 (mouse orthologue of hSac3) exhibit reduced PtdIns(3,5)P 2 levels (Chow et al, 2007), indicating that both mammalian and yeast Fig4 phosphatases may indeed have a role in PtdIns(3,5)P 2 synthesis.…”

Mouse Forward Genetics in the Study of the Peripheral Nervous System and Human Peripheral Neuropathy

“…The pale tremor mouse (Fig. 2a) exhibits motor and sensory neurodegeneration, and carries a mutation in the phosphatase Fig 4. The substrate of Fig4, phosphatidylinositol-2,5-bisphosphate (PtdIns(3,5)P 2 ), is important to endosomal membrane trafficking [38]. Vps54 is a member of the Golgi Associated Retrograde Protein (GARP) complex, which functions in endosomal trafficking [39]; the Vps54 mutation in the wobbler (wr) strain results in motoneuron disease [40].…”

“…2b) is particularly exciting because Fig4 was not previously associated with PNS pathology. In addition to demonstrating essential Fig4 function in the PNS, the mapping of the pale tremor lesion led to the discovery of four independent mutations in human patients with CMT, now designated CMT4J [38].…”