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 language | English |
|---|---|
| Pages (from-to) | 590-601 |
| Number of pages | 12 |
| Journal | American Journal of Human Genetics |
| Volume | 95 |
| Issue number | 5 |
| DOIs | |
| State | Published - 2014 |
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ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
Cite this
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 journal › Article
}
TY - JOUR
T1 - Truncating and missense mutations in IGHMBP2 cause Charcot-Marie Tooth disease type 2
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
Y1 - 2014
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84922331375&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84922331375&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2014.10.002
DO - 10.1016/j.ajhg.2014.10.002
M3 - Article
VL - 95
SP - 590
EP - 601
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 5
ER -