Brain, Vol. 126, No. 3, 590-597,
March 2003
© 2003 Guarantors of Brain
doi: 10.1093/brain/awg059
Mutations in the neurofilament light chain gene (NEFL) cause early onset severe Charcot–Marie–Tooth disease
1 Molecular Genetics Department, Flanders Interuniversity Institute for Biotechnology and 2 Laboratory of Neuropathology and Electronmicroscopy, Born-Bunge Foundation, University of Antwerp, Antwerp, 3 Division of Neurology, University Hospital of Antwerp, Edegem, Belgium, Departments of 4 Molecular and Human Genetics, and 5 Pediatrics, Baylor College of Medicine, Houston, TX, Departments of 6 Neurology and 7 Pathology and Laboratory Medicine, The University of Texas—Houston Medical School, Texas, 8 Department of Genetics, Credit Valley Hospital, Ontario, 9 Department of Neurology, Wayne State University School of Medicine, Detroit, MI, 10 Lutheran General Hospital, Park Ridge, IL, USA, 11 Laboratory of Molecular Pathology and 12 Department of Neurology, Sofia Medical University, Sofia, Bulgaria
Correspondence to: Professor Dr Vincent Timmerman, PhD, Peripheral Neuropathy Group, Molecular Genetics Department (VIB8), University of Antwerp (UIA), Universiteitsplein 1, B-2610 Antwerpen, Belgium E-mail: vincent.timmerman{at}ua.ac.be
Neurofilament light chain polypeptide (NEFL) is one of the most abundant cytoskeletal components of the neuron. Mutations in the NEFL gene were recently reported as a cause for autosomal dominant Charcot–Marie–Tooth type 2E (CMT2E) linked to chromosome 8p21. In order to investigate the frequency and phenotypic consequences of NEFL mutations, we screened 323 patients with CMT or related peripheral neuropathies. We detected six disease associated missense mutations and one 3-bp in-frame deletion clustered in functionally defined domains of the NEFL protein. Patients have an early onset and often a severe clinical phenotype. Electrophysiological examination shows moderately to severely slowed nerve conduction velocities. We report the first nerve biopsy of a CMT patient with a de novo missense mutation in NEFL, and found an axonal pathology with axonal regeneration clusters and onion bulb formations. Our findings provide further evidence that the clinical variation observed in CMT depends on the gene mutated and the specific type of mutation, and we also suggest that NEFL mutations need to be considered in the molecular evaluation of patients with sporadic or dominantly inherited CMT.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  K. G. Claeys, S. Zuchner, M. Kennerson, J. Berciano, A. Garcia, K. Verhoeven, E. Storey, J. R. Merory, H. M. E. Bienfait, M. Lammens, et al. Phenotypic spectrum of dynamin 2 mutations in Charcot-Marie-Tooth neuropathy Brain, July 1, 2009; 132(7): 1741 - 1752. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Kudryashova, J. Wu, L. A. Havton, and M. J. Spencer Deficiency of the E3 ubiquitin ligase TRIM32 in mice leads to a myopathy with a neurogenic component Hum. Mol. Genet., April 1, 2009; 18(7): 1353 - 1367. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Zhai, H. Lin, J.-P. Julien, and W. W. Schlaepfer Disruption of neurofilament network with aggregation of light neurofilament protein: a common pathway leading to motor neuron degeneration due to Charcot Marie Tooth disease-linked mutations in NFL and HSPB1 Hum. Mol. Genet., December 15, 2007; 16(24): 3103 - 3116. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. E. Pleasure Dwindling Indications for Sural Nerve Biopsy Arch Neurol, July 1, 2007; 64(7): 935 - 936. [Full Text] [PDF]
|
|
|
|
|
|
G. Miltenberger-Miltenyi, A. R. Janecke, J. V. Wanschitz, V. Timmerman, C. Windpassinger, M. Auer-Grumbach, and W. N. Loscher Clinical and Electrophysiological Features in Charcot-Marie-Tooth Disease With Mutations in the NEFL Gene Arch Neurol, July 1, 2007; 64(7): 966 - 970. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.M.E. Bienfait, F. Baas, J. H.T.M. Koelman, R. J. de Haan, B. G.M. van Engelen, A. A.W.M. Gabreels-Festen, B. W. Ongerboer de Visser, F. Meggouh, M. A.J. Weterman, P. De Jonghe, et al. Phenotype of Charcot-Marie-Tooth disease Type 2 Neurology, May 15, 2007; 68(20): 1658 - 1667. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. M. Fabrizi, T. Cavallaro, C. Angiari, I. Cabrini, F. Taioli, G. Malerba, L. Bertolasi, and N. Rizzuto Charcot-Marie-Tooth disease type 2E, a disorder of the cytoskeleton Brain, February 1, 2007; 130(2): 394 - 403. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Yuan, M. V. Rao, T. Sasaki, Y. Chen, A. Kumar, Veeranna, R. K. H. Liem, J. Eyer, A. C. Peterson, J.-P. Julien, et al. {alpha}-Internexin Is Structurally and Functionally Associated with the Neurofilament Triplet Proteins in the Mature CNS J. Neurosci., September 27, 2006; 26(39): 10006 - 10019. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Verhoeven, K. G. Claeys, S. Zuchner, J. M. Schroder, J. Weis, C. Ceuterick, A. Jordanova, E. Nelis, E. De Vriendt, M. Van Hul, et al. MFN2 mutation distribution and genotype/phenotype correlation in Charcot-Marie-Tooth type 2 Brain, August 1, 2006; 129(8): 2093 - 2102. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Sasaki, T. Gotow, M. Shiozaki, F. Sakaue, T. Saito, J.-P. Julien, Y. Uchiyama, and S.-I. Hisanaga Aggregate formation and phosphorylation of neurofilament-L Pro22 Charcot-Marie-Tooth disease mutants Hum. Mol. Genet., March 15, 2006; 15(6): 943 - 952. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ackerley, P. A. James, A. Kalli, S. French, K. E. Davies, and K. Talbot A mutation in the small heat-shock protein HSPB1 leading to distal hereditary motor neuronopathy disrupts neurofilament assembly and the axonal transport of specific cellular cargoes Hum. Mol. Genet., January 15, 2006; 15(2): 347 - 354. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Bolis, S. Coviello, S. Bussini, G. Dina, C. Pardini, S. C. Previtali, M. Malaguti, P. Morana, U. Del Carro, M. L. Feltri, et al. Loss of Mtmr2 Phosphatase in Schwann Cells But Not in Motor Neurons Causes Charcot-Marie-Tooth Type 4B1 Neuropathy with Myelin Outfoldings J. Neurosci., September 14, 2005; 25(37): 8567 - 8577. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Pleasure Chaperoning Motor Neurons Arch Neurol, August 1, 2005; 62(8): 1193 - 1193. [Full Text] [PDF]
|
|
|
|
 |
|
 A D. Sandre-Giovannoli, V Delague, T Hamadouche, M Chaouch, M Krahn, I Boccaccio, T Maisonobe, E Chouery, R Jabbour, S Atweh, et al. Homozygosity mapping of autosomal recessive demyelinating Charcot-Marie-Tooth neuropathy (CMT4H) to a novel locus on chromosome 12p11.21-q13.11 J. Med. Genet., March 1, 2005; 42(3): 260 - 265. [Full Text] [PDF]
|
|
|
|
|
|
A. Kochanski, M. Kennerson, M. Kawulak, B. Ryniewicz, K. Rowinska-Marcinska, G. Walizada, A. Nowakowski, I. Hausmanowa-Petrusewicz, and G. A. Nicholson Mild early onset axonal Charcot-Marie-Tooth disease not linked to other axonal Charcot-Marie-Tooth loci Neurology, February 8, 2005; 64(3): 533 - 535. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Perez-Olle, S. T. Jones, and R. K.H. Liem Phenotypic analysis of neurofilament light gene mutations linked to Charcot-Marie-Tooth disease in cell culture models Hum. Mol. Genet., October 1, 2004; 13(19): 2207 - 2220. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Bissar-Tadmouri, E. Nelis, S. Zuchner, Y. Parman, F. Deymeer, P. Serdaroglu, P. De Jonghe, V. Van Gerwen, V. Timmerman, J. M. Schroder, et al. Absence of KIF1B mutation in a large Turkish CMT2A family suggests involvement of a second gene Neurology, May 11, 2004; 62(9): 1522 - 1525. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. M. Fabrizi, T. Cavallaro, C. Angiari, L. Bertolasi, I. Cabrini, M. Ferrarini, and N. Rizzuto Giant axon and neurofilament accumulation in Charcot-Marie-Tooth disease type 2E Neurology, April 27, 2004; 62(8): 1429 - 1431. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. T. Helfand, L. Chang, and R. D. Goldman Intermediate filaments are dynamic and motile elements of cellular architecture J. Cell Sci., January 15, 2004; 117(2): 133 - 141. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Yuan, M. V. Rao, A. Kumar, J.-P. Julien, and R. A. Nixon Neurofilament Transport In Vivo Minimally Requires Hetero-Oligomer Formation J. Neurosci., October 15, 2003; 23(28): 9452 - 9458. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. C. Previtali, B. Zerega, D. L. Sherman, P. J. Brophy, G. Dina, R. H.M. King, M. M. Salih, L. Feltri, A. Quattrini, R. Ravazzolo, et al. Myotubularin-related 2 protein phosphatase and neurofilament light chain protein, both mutated in CMT neuropathies, interact in peripheral nerve Hum. Mol. Genet., July 15, 2003; 12(14): 1713 - 1723. [Abstract] [Full Text] [PDF]
|
|