Journal
HUMAN MOLECULAR GENETICS
Volume 23, Issue 10, Pages 2511-2526Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddt643
Keywords
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Funding
- Ulverscroft Foundation
- Child Health Research Appeal Trust
- Action Medical Research
- University of London Central Research Fund
- Rosetrees Trust
- National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at Great Ormond Street Hospital for Children NHS Foundation Trust (GOSH) and University College London (UCL)
- Great Ormond Street Hospital Children's Charity
- Wellcome Trust
- Medical Research Council UK
- Action Medical Research Training Fellowship
- NIHR BRC at GOSH and UCL
- UCL
- Fight for Sight [1976] Funding Source: researchfish
- Great Ormond Street Hospital Childrens Charity [V1257, V1239, V1296] Funding Source: researchfish
- Medical Research Council [MC_PC_15004, G0700089] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0513-10008] Funding Source: researchfish
- Rosetrees Trust [M257] Funding Source: researchfish
- MRC [MC_PC_15004, G0700089] Funding Source: UKRI
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Ocular coloboma is a congenital defect resulting from failure of normal closure of the optic fissure during embryonic eye development. This birth defect causes childhood blindness worldwide, yet the genetic etiology is poorly understood. Here, we identified a novel homozygous mutation in the SALL2 gene in members of a consanguineous family affected with non-syndromic ocular coloboma variably affecting the iris and retina. This mutation, c.85GT, introduces a premature termination codon (p.Glu29) predicted to truncate the SALL2 protein so that it lacks three clusters of zinc-finger motifs that are essential for DNA-binding activity. This discovery identifies SALL2 as the third member of the Drosophila homeotic Spalt-like family of developmental transcription factor genes implicated in human disease. SALL2 is expressed in the developing human retina at the time of, and subsequent to, optic fissure closure. Analysis of Sall2-deficient mouse embryos revealed delayed apposition of the optic fissure margins and the persistence of an anterior retinal coloboma phenotype after birth. Sall2-deficient embryos displayed correct posterior closure toward the optic nerve head, and upon contact of the fissure margins, dissolution of the basal lamina occurred and PAX2, known to be critical for this process, was expressed normally. Anterior closure was disrupted with the fissure margins failing to meet, or in some cases misaligning leading to a retinal lesion. These observations demonstrate, for the first time, a role for SALL2 in eye morphogenesis and that loss of function of the gene causes ocular coloboma in humans and mice.
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