GPSM2 mutations cause the brain malformations and hearing loss in Chudley-McCullough syndrome

Dan Doherty, Albert E. Chudley, Gail Coghlan, Gisele E. Ishak, A. Micheil Innes, Edmond G. Lemire, R. Curtis Rogers, Aizeddin A. Mhanni, Ian G. Phelps, Steven J M Jones, Shing H. Zhan, Anthony P. Fejes, Hashem Shahin, Moien Kanaan, Hatice Akay, Mustafa Tekin, Barbara Triggs-Raine, Teresa Zelinski

Research output: Contribution to journalArticle

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Abstract

Autosomal-recessive inheritance, severe to profound sensorineural hearing loss, and partial agenesis of the corpus callosum are hallmarks of the clinically well-established Chudley-McCullough syndrome (CMS). Although not always reported in the literature, frontal polymicrogyria and gray matter heterotopia are uniformly present, whereas cerebellar dysplasia, ventriculomegaly, and arachnoid cysts are nearly invariant. Despite these striking brain malformations, individuals with CMS generally do not present with significant neurodevelopmental abnormalities, except for hearing loss. Homozygosity mapping and whole-exome sequencing of DNA from affected individuals in eight families (including the family in the first report of CMS) revealed four molecular variations (two single-base deletions, a nonsense mutation, and a canonical splice-site mutation) in the G protein-signaling modulator 2 gene, GPSM2, that underlie CMS. Mutations in GPSM2 have been previously identified in people with profound congenital nonsyndromic hearing loss (NSHL). Subsequent brain imaging of these individuals revealed frontal polymicrogyria, abnormal corpus callosum, and gray matter heterotopia, consistent with a CMS diagnosis, but no ventriculomegaly. The gene product, GPSM2, is required for orienting the mitotic spindle during cell division in multiple tissues, suggesting that the sensorineural hearing loss and characteristic brain malformations of CMS are due to defects in asymmetric cell divisions during development.

Original languageEnglish
Pages (from-to)1088-1093
Number of pages6
JournalAmerican Journal of Human Genetics
Volume90
Issue number6
DOIs
StatePublished - Jun 8 2012

Fingerprint

Hearing Loss
Mutation
Brain
Sensorineural Hearing Loss
Asymmetric Cell Division
Exome
Arachnoid Cysts
Spindle Apparatus
Corpus Callosum
Nonsense Codon
DNA Sequence Analysis
GTP-Binding Proteins
Neuroimaging
Cell Division
Genes
Chudley-Mccullough syndrome

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Doherty, D., Chudley, A. E., Coghlan, G., Ishak, G. E., Innes, A. M., Lemire, E. G., ... Zelinski, T. (2012). GPSM2 mutations cause the brain malformations and hearing loss in Chudley-McCullough syndrome. American Journal of Human Genetics, 90(6), 1088-1093. https://doi.org/10.1016/j.ajhg.2012.04.008

GPSM2 mutations cause the brain malformations and hearing loss in Chudley-McCullough syndrome. / Doherty, Dan; Chudley, Albert E.; Coghlan, Gail; Ishak, Gisele E.; Innes, A. Micheil; Lemire, Edmond G.; Rogers, R. Curtis; Mhanni, Aizeddin A.; Phelps, Ian G.; Jones, Steven J M; Zhan, Shing H.; Fejes, Anthony P.; Shahin, Hashem; Kanaan, Moien; Akay, Hatice; Tekin, Mustafa; Triggs-Raine, Barbara; Zelinski, Teresa.

In: American Journal of Human Genetics, Vol. 90, No. 6, 08.06.2012, p. 1088-1093.

Research output: Contribution to journalArticle

Doherty, D, Chudley, AE, Coghlan, G, Ishak, GE, Innes, AM, Lemire, EG, Rogers, RC, Mhanni, AA, Phelps, IG, Jones, SJM, Zhan, SH, Fejes, AP, Shahin, H, Kanaan, M, Akay, H, Tekin, M, Triggs-Raine, B & Zelinski, T 2012, 'GPSM2 mutations cause the brain malformations and hearing loss in Chudley-McCullough syndrome', American Journal of Human Genetics, vol. 90, no. 6, pp. 1088-1093. https://doi.org/10.1016/j.ajhg.2012.04.008
Doherty, Dan ; Chudley, Albert E. ; Coghlan, Gail ; Ishak, Gisele E. ; Innes, A. Micheil ; Lemire, Edmond G. ; Rogers, R. Curtis ; Mhanni, Aizeddin A. ; Phelps, Ian G. ; Jones, Steven J M ; Zhan, Shing H. ; Fejes, Anthony P. ; Shahin, Hashem ; Kanaan, Moien ; Akay, Hatice ; Tekin, Mustafa ; Triggs-Raine, Barbara ; Zelinski, Teresa. / GPSM2 mutations cause the brain malformations and hearing loss in Chudley-McCullough syndrome. In: American Journal of Human Genetics. 2012 ; Vol. 90, No. 6. pp. 1088-1093.
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