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Hum Mutat. 2017 Aug;38(8):942-946. doi: 10.1002/humu.23246. Epub 2017 Jun 6.

A recurrent de novo mutation in ACTG1 causes isolated ocular coloboma.

Author information

1
The Roslin Institute and R(D)SVS, University of Edinburgh, Easter Bush Campus, Midlothian, UK.
2
MRC Human Genetics Unit, IGMM, University of Edinburgh, Western General Hospital, Edinburgh, UK.
3
Institut für Humangenetik Lübeck, Universitätsklinikum Schleswig-Holstein, Lübeck, Germany.
4
Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire, UK.

Abstract

Ocular coloboma (OC) is a defect in optic fissure closure and is a common cause of severe congenital visual impairment. Bilateral OC is primarily genetically determined and shows marked locus heterogeneity. Whole-exome sequencing (WES) was used to analyze 12 trios (child affected with OC and both unaffected parents). This identified de novo mutations in 10 different genes in eight probands. Three of these genes encoded proteins associated with actin cytoskeleton dynamics: ACTG1, TWF1, and LCP1. Proband-only WES identified a second unrelated individual with isolated OC carrying the same ACTG1 allele, encoding p.(Pro70Leu). Both individuals have normal neurodevelopment with no extra-ocular signs of Baraitser-Winter syndrome. We found this mutant protein to be incapable of incorporation into F-actin. The LCP1 and TWF1 variants each resulted in only minor disturbance of actin interactions, and no further plausibly causative variants were identified in these genes on resequencing 380 unrelated individuals with OC.

KEYWORDS:

ACTG1; eye development; ocular coloboma; tissue fusion

PMID:
28493397
PMCID:
PMC5518294
DOI:
10.1002/humu.23246
[Indexed for MEDLINE]
Free PMC Article

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