The instability of the BTB-KELCH protein Gigaxonin causes Giant Axonal Neuropathy and constitutes a new penetrant and specific diagnostic test

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• 作者：Alexia Boizot (1) (2)
  Yasmina Talmat-Amar (1) (2)
  Deborah Morrogh (3)
  Nancy L Kuntz (4)
  Cecile Halbert (5)
  Brigitte Chabrol (5)
  Henry Houlden (6)
  Tanya Stojkovic (7)
  Brenda A Schulman (8)
  Bernd Rautenstrauss (10) (9)
  Pascale Bomont (1) (2)
  
  1. Atip-Avenir team ; Inserm U1051 ; Institut des Neurosciences de Montpellier ; Montpellier ; France
  2. Universit茅 de Montpellier1&2 ; Montpellier ; France
  3. NE Thames Regional Genetics Service ; Great Ormond Street Hospital ; York House Queen Square ; London ; UK
  4. Northwestern University Feinberg School of Medicine ; Chicago ; USA
  5. Service de Neurologie P茅diatrique ; H么pital d鈥橢nfants ; CHU Timone ; Marseille ; France
  6. Department of Molecular Neuroscience and The MRC centre for Neuromuscular Diseases ; Institute of Neurology ; Queen Square ; London ; UK
  7. AP-HP ; G-H Piti茅-Salp锚tri猫re ; Institut de Myologie ; Paris ; France
  8. Howard Hughes Medical Institute ; Department of Structural Biology ; St. Jude Children鈥檚 Research Hospital ; Memphis ; Tennessee ; USA
  10. Ludwig-Maximilians-University Friedrich-Baur-Institut ; M眉nchen ; Germany
  9. Medizinisch Genetisches Zentrum Bayerstrasse ; M眉nchen ; Germany
  
• 关键词：CMT2 ; GAN ; Diagnosis ; Gigaxonin ; E3 ligase ; Modelization ; Instability
• 刊名：Acta Neuropathologica Communications
• 出版年：2014
• 出版时间：December 2014
• 年：2014
• 卷：2
• 期：1
• 全文大小：1,087 KB
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• 刊物主题：Neurosciences;
• 出版者：BioMed Central
• ISSN：2051-5960

文摘

Background The BTB-KELCH protein Gigaxonin plays key roles in sustaining neuron survival and cytoskeleton architecture. Indeed, recessive mutations in the Gigaxonin-encoding gene cause Giant Axonal Neuropathy (GAN), a severe neurodegenerative disorder characterized by a wide disorganization of the Intermediate Filament network. Growing evidences suggest that GAN is a continuum with the peripheral neuropathy Charcot-Marie-Tooth diseases type 2 (CMT2). Sharing similar sensory-motor alterations and aggregation of Neurofilaments, few reports have revealed that GAN and some CMT2 forms can be misdiagnosed on clinical and histopathological examination. The goal of this study is to propose a new differential diagnostic test for GAN/CMT2. Moreover, we aim at identifying the mechanisms causing the loss-of-function of Gigaxonin, which has been proposed to bind CUL3 and substrates as part of an E3 ligase complex. Results We establish that determining Gigaxonin level constitutes a very valuable diagnostic test in discriminating new GAN cases from clinically related inherited neuropathies. Indeed, in a set of seven new families presenting a neuropathy resembling GAN/CMT2, only five exhibiting a reduced Gigaxonin abundance have been subsequently genetically linked to GAN. Generating the homology modeling of Gigaxonin, we suggest that disease mutations would lead to a range of defects in Gigaxonin stability, impairing its homodimerization, BTB or KELCH domain folding, or CUL3 and substrate binding. We further demonstrate that regardless of the mutations or the severity of the disease, Gigaxonin abundance is severely reduced in all GAN patients due to both mRNA and protein instability mechanisms. Conclusions In this study, we developed a new penetrant and specific test to diagnose GAN among a set of individuals exhibiting CMT2 of unknown etiology to suggest that the prevalence of GAN is probably under-evaluated among peripheral neuropathies. We propose to use this new test in concert with the clinical examination and prior to the systematic screening of GAN mutations that has shown strong limitations for large deletions. Combining the generation of the structural modeling of Gigaxonin to an analysis of Gigaxonin transcripts and proteins in patients, we provide the first evidences of the instability of this E3 ligase adaptor in disease.