生物谷報道：在美國密執(zhí)安大學(xué)一個研究實(shí)驗(yàn)室中,，小鼠的一種自發(fā)突變的出現(xiàn)，使研究人員發(fā)現(xiàn)了造成一種形式的被稱為“腓骨肌萎縮癥”（Charcot–Marie–Tooth）的遺傳性神經(jīng)退化疾病的基因,。
這種被稱為“pale tremor”的小鼠（發(fā)生了一種多器官神經(jīng)退化）在酵母基因Fig4的一個等位基因上發(fā)生突變,，該基因是維持正常水平的信號作用類脂PI(3,5)P2所必需的。在這項工作之前,，一直沒有證據(jù)表明含量較低的信號作用化合物PI(3,5)P2在神經(jīng)維護(hù)中有某種具體的作用,。
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: [email protected]).
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.
