Truncating and missense mutations in IGHMBP2 cause Charcot-Marie Tooth disease type 2

Ellen Cottenie, Andrzej Kochanski, Albena Jordanova, Boglarka Bansagi, Magdalena Zimon, Alejandro Horga, Zane Jaunmuktane, Paola Saveri, Vedrana Milic Rasic, Jonathan Baets, Marina Bartsakoulia, Rafal Ploski, Pawel Teterycz, Milos Nikolic, Ros Quinlivan, Matilde Laura, Mary G. Sweeney, Franco Taroni, Michael P. Lunn, Isabella Moroni & 20 others Michael Gonzalez, Michael G. Hanna, Conceicao Bettencourt, Elodie Chabrol, Andre Franke, Katja Von Au, Markus Schilhabel, Dagmara Kabzińska, Irena Hausmanowa-Petrusewicz, Sebastian Brandner, Siew Choo Lim, Haiwei Song, Byung Ok Choi, Rita Horvath, Ki Wha Chung, Stephan L Zuchner, Davide Pareyson, Matthew Harms, Mary M. Reilly, Henry Houlden

Research output: Contribution to journalArticle

32 Citations (Scopus)

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-mbinding 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 50 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.

Original languageEnglish
Pages (from-to)590-601
Number of pages12
JournalAmerican Journal of Human Genetics
Volume95
Issue number5
DOIs
StatePublished - 2014

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Charcot-Marie-Tooth Disease
Missense Mutation
Immunoglobulins
Proteins
Mutation
Spinal Muscular Atrophies of Childhood
Exome
Frameshift Mutation
Siblings
Exons
Fibroblasts
Phenotype

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Cottenie, E., Kochanski, A., Jordanova, A., Bansagi, B., Zimon, M., Horga, A., ... Houlden, H. (2014). Truncating and missense mutations in IGHMBP2 cause Charcot-Marie Tooth disease type 2. American Journal of Human Genetics, 95(5), 590-601. https://doi.org/10.1016/j.ajhg.2014.10.002

Truncating and missense mutations in IGHMBP2 cause Charcot-Marie Tooth disease type 2. / Cottenie, Ellen; Kochanski, Andrzej; Jordanova, Albena; Bansagi, Boglarka; Zimon, Magdalena; Horga, Alejandro; Jaunmuktane, Zane; Saveri, Paola; Rasic, Vedrana Milic; Baets, Jonathan; Bartsakoulia, Marina; Ploski, Rafal; Teterycz, Pawel; Nikolic, Milos; Quinlivan, Ros; Laura, Matilde; Sweeney, Mary G.; Taroni, Franco; Lunn, Michael P.; Moroni, Isabella; Gonzalez, Michael; Hanna, Michael G.; Bettencourt, Conceicao; Chabrol, Elodie; Franke, Andre; Von Au, Katja; Schilhabel, Markus; Kabzińska, Dagmara; Hausmanowa-Petrusewicz, Irena; Brandner, Sebastian; Lim, Siew Choo; Song, Haiwei; Choi, Byung Ok; Horvath, Rita; Chung, Ki Wha; Zuchner, Stephan L; Pareyson, Davide; Harms, Matthew; Reilly, Mary M.; Houlden, Henry.

In: American Journal of Human Genetics, Vol. 95, No. 5, 2014, p. 590-601.

Research output: Contribution to journalArticle

Cottenie, E, Kochanski, A, Jordanova, A, Bansagi, B, Zimon, M, Horga, A, Jaunmuktane, Z, Saveri, P, Rasic, VM, Baets, J, Bartsakoulia, M, Ploski, R, Teterycz, P, Nikolic, M, Quinlivan, R, Laura, M, Sweeney, MG, Taroni, F, Lunn, MP, Moroni, I, Gonzalez, M, Hanna, MG, Bettencourt, C, Chabrol, E, Franke, A, Von Au, K, Schilhabel, M, Kabzińska, D, Hausmanowa-Petrusewicz, I, Brandner, S, Lim, SC, Song, H, Choi, BO, Horvath, R, Chung, KW, Zuchner, SL, Pareyson, D, Harms, M, Reilly, MM & Houlden, H 2014, 'Truncating and missense mutations in IGHMBP2 cause Charcot-Marie Tooth disease type 2', American Journal of Human Genetics, vol. 95, no. 5, pp. 590-601. https://doi.org/10.1016/j.ajhg.2014.10.002
Cottenie, Ellen ; Kochanski, Andrzej ; Jordanova, Albena ; Bansagi, Boglarka ; Zimon, Magdalena ; Horga, Alejandro ; Jaunmuktane, Zane ; Saveri, Paola ; Rasic, Vedrana Milic ; Baets, Jonathan ; Bartsakoulia, Marina ; Ploski, Rafal ; Teterycz, Pawel ; Nikolic, Milos ; Quinlivan, Ros ; Laura, Matilde ; Sweeney, Mary G. ; Taroni, Franco ; Lunn, Michael P. ; Moroni, Isabella ; Gonzalez, Michael ; Hanna, Michael G. ; Bettencourt, Conceicao ; Chabrol, Elodie ; Franke, Andre ; Von Au, Katja ; Schilhabel, Markus ; Kabzińska, Dagmara ; Hausmanowa-Petrusewicz, Irena ; Brandner, Sebastian ; Lim, Siew Choo ; Song, Haiwei ; Choi, Byung Ok ; Horvath, Rita ; Chung, Ki Wha ; Zuchner, Stephan L ; Pareyson, Davide ; Harms, Matthew ; Reilly, Mary M. ; Houlden, Henry. / Truncating and missense mutations in IGHMBP2 cause Charcot-Marie Tooth disease type 2. In: American Journal of Human Genetics. 2014 ; Vol. 95, No. 5. pp. 590-601.
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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-mbinding 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 50 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.",
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AU - Cottenie, Ellen

AU - Kochanski, Andrzej

AU - Jordanova, Albena

AU - Bansagi, Boglarka

AU - Zimon, Magdalena

AU - Horga, Alejandro

AU - Jaunmuktane, Zane

AU - Saveri, Paola

AU - Rasic, Vedrana Milic

AU - Baets, Jonathan

AU - Bartsakoulia, Marina

AU - Ploski, Rafal

AU - Teterycz, Pawel

AU - Nikolic, Milos

AU - Quinlivan, Ros

AU - Laura, Matilde

AU - Sweeney, Mary G.

AU - Taroni, Franco

AU - Lunn, Michael P.

AU - Moroni, Isabella

AU - Gonzalez, Michael

AU - Hanna, Michael G.

AU - Bettencourt, Conceicao

AU - Chabrol, Elodie

AU - Franke, Andre

AU - Von Au, Katja

AU - Schilhabel, Markus

AU - Kabzińska, Dagmara

AU - Hausmanowa-Petrusewicz, Irena

AU - Brandner, Sebastian

AU - Lim, Siew Choo

AU - Song, Haiwei

AU - Choi, Byung Ok

AU - Horvath, Rita

AU - Chung, Ki Wha

AU - Zuchner, Stephan L

AU - Pareyson, Davide

AU - Harms, Matthew

AU - Reilly, Mary M.

AU - Houlden, Henry

PY - 2014

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