Journal
HUMAN MUTATION
Volume 38, Issue 8, Pages 942-946Publisher
WILEY
DOI: 10.1002/humu.23246
Keywords
ACTG1; eye development; ocular coloboma; tissue fusion
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Funding
- Fight for Sight (UK) [1590/1591]
- MRC University
- Wellcome Trust [WT091310]
- BBSRC [BB/F024347/1, BBS/E/D/10002071] Funding Source: UKRI
- MRC [MC_PC_U127561093, MR/K01563X/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BBS/E/D/10002071] Funding Source: researchfish
- Fight for Sight [1590/91] Funding Source: researchfish
- Medical Research Council [MC_PC_U127561093] Funding Source: researchfish
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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.
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