Journal article
Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J
Nature (London), Vol.448(7149), pp.68-72
07/05/2007
DOI: 10.1038/nature05876
PMCID: PMC2271033
PMID: 17572665
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 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.
Details
- Title: Subtitle
- Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J
- Creators
- Clement Y Chow - Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109, USAYanling Zhang - Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USAJames J Dowling - Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109, USANatsuko Jin - Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USAMaja Adamska - Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109, USAKensuke Shiga - Departments of Molecular and Human Genetics, Houston, Texas 77030, USAKinga Szigeti - Departments of Molecular and Human Genetics, Houston, Texas 77030, USAMichael E Shy - Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan 48201, USAJun Li - Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan 48201, USAXuebao Zhang - Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan 48201, USAJames R Lupski - Departments of Molecular and Human Genetics, Houston, Texas 77030, USALois S Weisman - Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USAMiriam H Meisler - Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA
- Resource Type
- Journal article
- Publication Details
- Nature (London), Vol.448(7149), pp.68-72
- DOI
- 10.1038/nature05876
- PMID
- 17572665
- PMCID
- PMC2271033
- ISSN
- 0028-0836
- eISSN
- 1476-4687
- Language
- English
- Date published
- 07/05/2007
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Iowa Neuroscience Institute
- Record Identifier
- 9984020651202771
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