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. 2012 Jun 8;90(6):1088-93.
doi: 10.1016/j.ajhg.2012.04.008. Epub 2012 May 10.

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

Collaborators, Affiliations

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

Dan Doherty et al. Am J Hum Genet. .

Erratum in

  • Am J Hum Genet. 2012 Jul 13;91(1):209

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.

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Figures

Figure 1
Figure 1
Characteristic Neuroimaging Features of GPSM2-related Chudley-McCullough Syndrome (A) illustrates posterior agenesis of the corpus callosum (bracket indicates remaining corpus callosum) and a quadrigeminal plate cistern cyst (white plus sign) causing mass effect on the cerebellum and tectum in individual 8A at 3 years of age. (B) illustrates severe ventriculomegaly (black asterisks) and frontal polymicrogyria (white arrows) in individual 8B at 6 months of age. (C) illustrates large frontal gray matter heterotopia (white arrowheads) located superior and medial to the enlarged lateral ventricles (black asterisks) in individual 8A at 3 years of age. (D) illustrates inferior cerebellar hemisphere dysplasia in individual 8B at 6 months of age. (E) and (F) illustrate a short corpus callosum (bracket indicates remaining corpus callosum) and a quadrigeminal plate cistern cyst (black plus sign) causing mass effect on the cerebellum and tectum as well as cerebellar hemisphere dysplasia in individual 9A (CG6 from Walsh et al.9) at 26 years of age. (G) and (H) illustrate similar findings in individual 10B (IV-2 from Yariz et al.10) at 12 years of age, although the corpus callosum is thinned posteriorly and dysplastic anteriorly, rather than short. (A) and (G) are sagittal T1-weighted images; (B)–(D), (F), and (H) are axial T2-weighted images, and (E) is a sagittal T2-weighted image.
Figure 2
Figure 2
GPSM2 Sequence Analysis and GPSM2 Schematic With the use of the primers specified in Table S2, genomic DNA from each subject was PCR-amplified, and the products were isolated and purified, as described in Supplemental Data. Sanger sequencing was conducted on both the forward and reverse strand; only the forward strand is shown here. The reference (ref.) sequence (NM_013296.4) is depicted directly below the variant sequence in each panel. (A) depicts the c.1471delG mutation identified in five subjects. (B) depicts the c.741delC homozygous mutation identified in three subjects. Two other study subjects were heterozygous for this mutation (sequence not shown). (C) depicts the c.1661C>A heterozygous mutation from one of the two subjects who was also heterozygous for c.741delC. (D) depicts the homozygous splice-site mutation identified in siblings 8A and 8B. (E) depicts the effect of the splice-site mutation on the splicing of exon 9. Primers in exons 8 and 9 generated a ∼200 base-pair (bp) product in the unaffected control, but no product in subjects 8A and 8B. Primers in exons 8 and 10 generated a ∼300 bp fragment in the control and a ∼200 bp product in subjects 8A and 8B, consistent with the loss of exon 9. Sequencing of this product revealed that exon 8 is spliced to exon 10 in the affected siblings (data not shown). The horizontal arrows indicate the primer positions; the vertical red arrow indicates the location of the splice-site mutation. “lad” indicates the ladder lane and “C” indicates the control lanes. The expected exon composition and size of the various products are indicated to the right of the gel. (F) depicts the positions of amino-acid variants that account for NSHL and CMS, and includes the mouse-engineered variant ΔC. Three of the variants occur within the seven tetratricopeptide repeat domains of GPSM2, and three within the four GoLoco motifs.

References

    1. Chudley A.E., McCullough C., McCullough D.W. Bilateral sensorineural deafness and hydrocephalus due to foramen of Monro obstruction in sibs: a newly described autosomal recessive disorder. Am. J. Med. Genet. 1997;68:350–356. - PubMed
    1. Hendriks Y.M.C., Laan L.A.E.M., Vielvoye G.J., van Haeringen A. Bilateral sensorineural deafness, partial agenesis of the corpus callosum, and arachnoid cysts in two sisters. Am. J. Med. Genet. 1999;86:183–186. - PubMed
    1. Lemire E.G., Stoeber G.P. Chudley-McCullough syndrome: bilateral sensorineural deafness, hydrocephalus, and other structural brain abnormalities. Am. J. Med. Genet. 2000;90:127–130. - PubMed
    1. Welch K.O., Tekin M., Nance W.E., Blanton S.H., Arnos K.S., Pandya A. Chudley-McCullough syndrome: expanded phenotype and review of the literature. Am. J. Med. Genet. A. 2003;119A:71–76. - PubMed
    1. Østergaard E., Pedersen V.F., Skriver E.B., Brøndum-Nielsen K. Brothers with Chudley-McCullough syndrome: sensorineural deafness, agenesis of the corpus callosum, and other structural brain abnormalities. Am. J. Med. Genet. A. 2004;124A:74–78. - PubMed

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