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Mutation of SALL2 causes recessive ocular coloboma in humans and mice

Mutation of SALL2 causes recessive ocular coloboma in humans and mice
Mutation of SALL2 causes recessive ocular coloboma in humans and mice
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.85G>T, 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.
0964-6906
2511–2526
Lakowski, Jorn
1856e739-982a-412a-87c7-abf1610f5384
Lakowski, Jorn
1856e739-982a-412a-87c7-abf1610f5384

Lakowski, Jorn (2014) Mutation of SALL2 causes recessive ocular coloboma in humans and mice. Human Molecular Genetics, 23 (10), 2511–2526. (doi:10.1093/hmg/ddt643).

Record type: Article

Abstract

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.85G>T, 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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e-pub ahead of print date: 9 January 2014
Published date: 15 May 2014

Identifiers

Local EPrints ID: 425769
URI: http://eprints.soton.ac.uk/id/eprint/425769
ISSN: 0964-6906
PURE UUID: 2e96af82-5fa2-42ec-aa86-c7373672aebe
ORCID for Jorn Lakowski: ORCID iD orcid.org/0000-0003-4214-7580

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Date deposited: 02 Nov 2018 17:30
Last modified: 22 Nov 2021 03:18

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