“腓骨肌萎缩症”基因的发现
生物谷报道：在美国密执安大学一个研究实验室中，小鼠的一种自发突变的出现，使研究人员发现了造成一种形式的被称为“腓骨肌萎缩症”（Charcot–Marie–Tooth）的遗传性神经退化疾病的基因。
这种被称为“pale tremor”的小鼠（发生了一种多器官神经退化）在酵母基因Fig4的一个等位基因上发生突变，该基因是维持正常水平的信号作用类脂PI(3,5)P2所必需的。在这项工作之前，一直没有证据表明含量较低的信号作用化合物PI(3,5)P2在神经维护中有某种具体的作用。
英文原文:
Nature 448, 68-72 (5 July 2007) | doi:10.1038/nature05876; Received 7 March 2007; Accepted 23 April 2007; Published online 17 June 2007
Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J
Clement Y. Chow1, Yanling Zhang2, James J. Dowling4, Natsuko Jin2, Maja Adamska1, Kensuke Shiga5, Kinga Szigeti5,7, Michael E. Shy9, Jun Li9,10, Xuebao Zhang9, James R. Lupski5,6,8, Lois S. Weisman2,3 & Miriam H. Meisler1
- Department of Human Genetics,
- Life Sciences Institute,
- Department of Cellular and Developmental Biology, and,
- Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109, USA
- Departments of Molecular and Human Genetics,
- Pediatrics, and,
- Neurology, Baylor College of Medicine
- Texas Children's Hospital, Houston, Texas 77030, USA
- Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA
- John D. Dingle VA Medical Center, Detroit, Michigan 48201, USA
Correspondence to: Miriam H. Meisler1 Correspondence and requests for materials should be addressed to M.H.M. (Email: meislerm@umich.edu).
Abstract
Membrane-bound phosphoinositides are signalling molecules that have a key role in vesicle trafficking in eukaryotic cells1. 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 yeast2. 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 ETn2
(early transposon 2
)3 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.
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