title: GPSM2 mutations cause the brain malformations and hearing loss in Chudley-McCullough syndrome.
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.
authors.affiliation: Department of Pediatrics, University of Washington, Seattle Children's Hospital, 98105, USA. ddoher@u.washington.edu
authors.forename: Dan
authors.initials: D
authors.lastname: Doherty
authors.forename: Albert E
authors.initials: AE
authors.lastname: Chudley
authors.forename: Gail
authors.initials: G
authors.lastname: Coghlan
authors.forename: Gisele E
authors.initials: GE
authors.lastname: Ishak
authors.forename: A Micheil
authors.initials: AM
authors.lastname: Innes
authors.forename: Edmond G
authors.initials: EG
authors.lastname: Lemire
authors.forename: R Curtis
authors.initials: RC
authors.lastname: Rogers
authors.forename: Aizeddin A
authors.initials: AA
authors.lastname: Mhanni
authors.forename: Ian G
authors.initials: IG
authors.lastname: Phelps
authors.forename: Steven J M
authors.initials: SJ
authors.lastname: Jones
authors.forename: Shing H
authors.initials: SH
authors.lastname: Zhan
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Fejes
authors.forename: Hashem
authors.initials: H
authors.lastname: Shahin
authors.forename: Moien
authors.initials: M
authors.lastname: Kanaan
authors.forename: Hatice
authors.initials: H
authors.lastname: Akay
authors.forename: Mustafa
authors.initials: M
authors.lastname: Tekin
authors.forename: Barbara
authors.initials: B
authors.lastname: Triggs-Raine
authors.forename: Teresa
authors.initials: T
authors.lastname: Zelinski
mesh_terms: D000293:Adolescent; D000328:Adult; D061085:Agenesis of Corpus Callosum / Q000235:genetics* / Q000473:pathology; D016080:Arachnoid Cysts / Q000235:genetics* / Q000473:pathology; D001921:Brain / Q000002:abnormalities* / Q000473:pathology; D001927:Brain Diseases / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005192:Family Health; D005260:Female; D017353:Gene Deletion; D006319:Hearing Loss, Sensorineural / Q000235:genetics* / Q000473:pathology; D006720:Homozygote; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D009154:Mutation; D017422:Sequence Analysis, DNA
chemical_list: C102754:GPSM2 protein, human; D047908:Intracellular Signaling Peptides and Proteins