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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-?-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.

SUBMITTER: Cottenie E 

PROVIDER: S-EPMC4225647 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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

Cottenie Ellen E   Kochanski Andrzej A   Jordanova Albena A   Bansagi Boglarka B   Zimon Magdalena M   Horga Alejandro A   Jaunmuktane Zane Z   Saveri Paola P   Rasic Vedrana Milic VM   Baets Jonathan J   Bartsakoulia Marina M   Ploski Rafal R   Teterycz Pawel P   Nikolic Milos M   Quinlivan Ros R   Laura Matilde M   Sweeney Mary G MG   Taroni Franco F   Lunn Michael P MP   Moroni Isabella I   Gonzalez Michael M   Hanna Michael G MG   Bettencourt Conceicao C   Chabrol Elodie E   Franke Andre A   von Au Katja K   Schilhabel Markus M   Kabzińska Dagmara D   Hausmanowa-Petrusewicz Irena I   Brandner Sebastian S   Lim Siew Choo SC   Song Haiwei H   Choi Byung-Ok BO   Horvath Rita R   Chung Ki-Wha KW   Zuchner Stephan S   Pareyson Davide D   Harms Matthew M   Reilly Mary M MM   Houlden Henry H  

American journal of human genetics 20141030 5


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  ...[more]

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