GPSM2 Mutations Cause the Brain Malformations and Hearing Loss in Chudley-McCullough Syndrome

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• 作者：Dan Doherty¹ ; ^{ddoher@u.washington.edu} ; Albert  ; E. Chudley² ; Gail Coghlan³ ; Gisele  ; E. Ishak⁴ ; A.  ; Micheil Innes⁵ ; Edmond  ; G. Lemire⁶ ; R.  ; Curtis Rogers⁷ ; Aizeddin  ; A. Mhanni² ; Ian  ; G. Phelps¹ ; Steven  ; J.M. Jones⁸ ; Shing  ; H. Zhan⁸ ; Anthony  ; P. Fejes⁸ ; Hashem Shahin⁹ ; Moien Kanaan⁹ ; Hatice Akay¹⁰ ; Mustafa Tekin¹¹ ; ¹² ; FORGE Canada Consortium¹³ ; Barbara Triggs-Raine² ; Teresa Zelinski² ; ³ ; ^{zelinski@cc.umanitoba.ca}
• 刊名：The American Journal of Human Genetics
• 出版年：2012
• 期刊代码：P22_00029297
• 类别：bio
• 出版时间：8 June, 2012
• 卷：90
• 期：6
• 页码：1088-1093
• 文件大小：493 K

摘要

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.