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 language | English |
|---|---|
| Pages (from-to) | 1088-1093 |
| Number of pages | 6 |
| Journal | American Journal of Human Genetics |
| Volume | 90 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 8 2012 |
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ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
Cite this
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 journal › Article
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TY - JOUR
T1 - GPSM2 mutations cause the brain malformations and hearing loss in Chudley-McCullough syndrome
AU - Doherty, Dan
AU - Chudley, Albert E.
AU - Coghlan, Gail
AU - Ishak, Gisele E.
AU - Innes, A. Micheil
AU - Lemire, Edmond G.
AU - Rogers, R. Curtis
AU - Mhanni, Aizeddin A.
AU - Phelps, Ian G.
AU - Jones, Steven J M
AU - Zhan, Shing H.
AU - Fejes, Anthony P.
AU - Shahin, Hashem
AU - Kanaan, Moien
AU - Akay, Hatice
AU - Tekin, Mustafa
AU - Triggs-Raine, Barbara
AU - Zelinski, Teresa
PY - 2012/6/8
Y1 - 2012/6/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84862128389&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84862128389&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2012.04.008
DO - 10.1016/j.ajhg.2012.04.008
M3 - Article
C2 - 22578326
AN - SCOPUS:84862128389
VL - 90
SP - 1088
EP - 1093
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 6
ER -