title: Mutation of SALL2 causes recessive ocular coloboma in humans and mice.
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.
authors.affiliation: Ulverscroft Vision Research Group.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kelberman
authors.forename: Lily
authors.initials: L
authors.lastname: Islam
authors.forename: Jörn
authors.initials: J
authors.lastname: Lakowski
authors.forename: Chiara
authors.initials: C
authors.lastname: Bacchelli
authors.forename: Estelle
authors.initials: E
authors.lastname: Chanudet
authors.forename: Francesco
authors.initials: F
authors.lastname: Lescai
authors.forename: Aara
authors.initials: A
authors.lastname: Patel
authors.forename: Elia
authors.initials: E
authors.lastname: Stupka
authors.forename: Anja
authors.initials: A
authors.lastname: Buck
authors.forename: Stephan
authors.initials: S
authors.lastname: Wolf
authors.forename: Philip L
authors.initials: PL
authors.lastname: Beales
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Jacques
authors.forename: Maria
authors.initials: M
authors.lastname: Bitner-Glindzicz
authors.forename: Alki
authors.initials: A
authors.lastname: Liasis
authors.forename: Ordan J
authors.initials: OJ
authors.lastname: Lehmann
authors.forename: Jürgen
authors.initials: J
authors.lastname: Kohlhase
authors.forename: Ken K
authors.initials: KK
authors.lastname: Nischal
authors.forename: Jane C
authors.initials: JC
authors.lastname: Sowden
mesh_terms: D000293:Adolescent; D000818:Animals; D002648:Child; D018389:Codon, Nonsense; D003103:Coloboma / Q000235:genetics*; D003241:Consanguinity; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins; D005123:Eye / Q000196:embryology / Q000473:pathology; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D005808:Genes, Recessive; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051762:PAX2 Transcription Factor / Q000235:genetics / Q000378:metabolism; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D018389:Codon, Nonsense; D004268:DNA-Binding Proteins; D005136:Eye Proteins; D018398:Homeodomain Proteins; D051762:PAX2 Transcription Factor; C497318:PAX2 protein, human; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins; C104147:SALL2 protein, human; D014157:Transcription Factors