title: Truncating and missense mutations in IGHMBP2 cause Charcot-Marie Tooth disease type 2.
abstract: Using a combination of exome sequencing and linkage analysis, we investigated an English family with two affected siblings in their 40s with recessive Charcot-Marie Tooth disease type 2 (CMT2). Compound heterozygous mutations in the immunoglobulin-helicase-μ-binding protein 2 (IGHMBP2) gene were identified. Further sequencing revealed a total of 11 CMT2 families with recessively inherited IGHMBP2 gene mutations. IGHMBP2 mutations usually lead to spinal muscular atrophy with respiratory distress type 1 (SMARD1), where most infants die before 1 year of age. The individuals with CMT2 described here, have slowly progressive weakness, wasting and sensory loss, with an axonal neuropathy typical of CMT2, but no significant respiratory compromise. Segregating IGHMBP2 mutations in CMT2 were mainly loss-of-function nonsense in the 5' region of the gene in combination with a truncating frameshift, missense, or homozygous frameshift mutations in the last exon. Mutations in CMT2 were predicted to be less aggressive as compared to those in SMARD1, and fibroblast and lymphoblast studies indicate that the IGHMBP2 protein levels are significantly higher in CMT2 than SMARD1, but lower than controls, suggesting that the clinical phenotype differences are related to the IGHMBP2 protein levels.
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; Department of Molecular Neurosciences, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Ellen
authors.initials: E
authors.lastname: Cottenie
authors.affiliation: Neuromuscular Unit, Mossakowski Medical Research Centre Polish Academy of Sciences, Centre of Biostructure, Medical University of Warsaw, Pawinskiego 5, 02-106 Warsaw, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Kochanski
authors.affiliation: VIB Department of Molecular Genetics, University of Antwerp, Antwerpen 2610, Belgium.
authors.forename: Albena
authors.initials: A
authors.lastname: Jordanova
authors.affiliation: Institute of Genetic Medicine, MRC Centre for Neuromuscular Diseases, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Boglarka
authors.initials: B
authors.lastname: Bansagi
authors.affiliation: VIB Department of Molecular Genetics, University of Antwerp, Antwerpen 2610, Belgium.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Zimon
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; Department of Molecular Neurosciences, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Horga
authors.affiliation: Division of Neuropathology and Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Zane
authors.initials: Z
authors.lastname: Jaunmuktane
authors.affiliation: Clinic of Central and Peripheral Degenerative Neuropathies Unit, IRCCS Foundation, C. Besta Neurological Institute, Via Celoria 11, 20133 Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Saveri
authors.affiliation: Clinic for Neurology and Psychiatry for Children and Youth, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia.
authors.forename: Vedrana Milic
authors.initials: VM
authors.lastname: Rasic
authors.affiliation: VIB Department of Molecular Genetics, University of Antwerp, Antwerpen 2610, Belgium; Laboratory of Neurogenetics, University of Antwerp, Antwerpen 2610, Belgium; Department of Neurology, Antwerp University Hospital, Antwerpen, Belgium.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Baets
authors.affiliation: Institute of Genetic Medicine, MRC Centre for Neuromuscular Diseases, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Marina
authors.initials: M
authors.lastname: Bartsakoulia
authors.affiliation: Department of Medical Genetics, Centre of Biostructure, Medical University of Warsaw, Pawinskiego 5, 02-106 Warsaw, Poland.
authors.forename: Rafal
authors.initials: R
authors.lastname: Ploski
authors.affiliation: Department of Medical Genetics, Centre of Biostructure, Medical University of Warsaw, Pawinskiego 5, 02-106 Warsaw, Poland.
authors.forename: Pawel
authors.initials: P
authors.lastname: Teterycz
authors.affiliation: University of Belgrade, Faculty of Medicine, 11000 Belgrade, Serbia.
authors.forename: Milos
authors.initials: M
authors.lastname: Nikolic
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Ros
authors.initials: R
authors.lastname: Quinlivan
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; Department of Molecular Neurosciences, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Matilde
authors.initials: M
authors.lastname: Laura
authors.affiliation: Neurogenetics Laboratory, The National Hospital for Neurology and Neurosurgery and UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Mary G
authors.initials: MG
authors.lastname: Sweeney
authors.affiliation: Unit of Genetics of Neurodegenerative and Metabolic Disease IRCCS Foundation, C. Besta Neurological Institute, Via Celoria 11, 20133 Milan, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Taroni
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lunn
authors.affiliation: Child Neurology Unit, IRCCS Foundation, C. Besta Neurological Institute, Via Celoria 11, 20133 Milan, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Moroni
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, FL 33136, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Gonzalez
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; Department of Molecular Neurosciences, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Hanna
authors.affiliation: Department of Molecular Neurosciences, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Conceicao
authors.initials: C
authors.lastname: Bettencourt
authors.affiliation: Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Elodie
authors.initials: E
authors.lastname: Chabrol
authors.affiliation: Christian-Albrechts-University, 24118 Kiel, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.affiliation: SPZ Pediatric Neurology, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: von Au
authors.affiliation: Christian-Albrechts-University, 24118 Kiel, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Schilhabel
authors.affiliation: Neuromuscular Unit, Mossakowski Medical Research Centre Polish Academy of Sciences, Centre of Biostructure, Medical University of Warsaw, Pawinskiego 5, 02-106 Warsaw, Poland.
authors.forename: Dagmara
authors.initials: D
authors.lastname: Kabzińska
authors.affiliation: Neuromuscular Unit, Mossakowski Medical Research Centre Polish Academy of Sciences, Centre of Biostructure, Medical University of Warsaw, Pawinskiego 5, 02-106 Warsaw, Poland.
authors.forename: Irena
authors.initials: I
authors.lastname: Hausmanowa-Petrusewicz
authors.affiliation: Division of Neuropathology and Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brandner
authors.affiliation: Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673.
authors.forename: Siew Choo
authors.initials: SC
authors.lastname: Lim
authors.affiliation: Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673; Life Sciences Institute, Zhejiang University, Hangzhou 310058, People's Republic of China.
authors.forename: Haiwei
authors.initials: H
authors.lastname: Song
authors.affiliation: Department of Neurology, Sungkyunkwan University School of Medicine, Seoul 137-710, Korea.
authors.forename: Byung-Ok
authors.initials: BO
authors.lastname: Choi
authors.affiliation: Institute of Genetic Medicine, MRC Centre for Neuromuscular Diseases, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Rita
authors.initials: R
authors.lastname: Horvath
authors.affiliation: Department of Biological Science, Kongju National University, Chungnam 134-701, Korea.
authors.forename: Ki-Wha
authors.initials: KW
authors.lastname: Chung
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, FL 33136, USA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Zuchner
authors.affiliation: Clinic of Central and Peripheral Degenerative Neuropathies Unit, IRCCS Foundation, C. Besta Neurological Institute, Via Celoria 11, 20133 Milan, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Pareyson
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Harms
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; Department of Molecular Neurosciences, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Mary M
authors.initials: MM
authors.lastname: Reilly
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; Department of Molecular Neurosciences, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; Neurogenetics Laboratory, The National Hospital for Neurology and Neurosurgery and UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK. Electronic address: h.houlden@ucl.ac.uk.
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
mesh_terms: D000328:Adult; D001483:Base Sequence; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000473:pathology; D002874:Chromosome Mapping; D059472:Exome / Q000235:genetics*; D005260:Female; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D025941:Protein Interaction Mapping; D017422:Sequence Analysis, DNA; D013497:Sural Nerve / Q000473:pathology