Recurrence of <i>SOX2</i> anophthalmia syndrome with gonosomal mosaicism in a phenotypically normal mother

Faivre, Laurence; Williamson, Kathleen A.; Faber, Valérie; Laurent, Nicole; Grimaldi, M.; Thauvin‐Robinet, Christel; Durand, C.; Mugneret, Francine; Gouyon, Jean‐Bernard; Bron, Alain M.; Huet, Frédéric; Hayward, Caroline; Heyningen, Veronica van; FitzPatrick, David R.

doi:10.1002/ajmg.a.31114

Cited by 53 publications

(60 citation statements)

References 7 publications

(8 reference statements)

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“…In severe ocular malformations, the majority of the mutations identified in the Sox2 locus are frameshift or nonsense mutations and are expected to produce a truncated Sox2 protein (7). However, missense mutations that lead to amino acid changes have been found in three cases (8,28,29). Intriguingly, two of these three missense mutations are predicted to alter the conserved residues in helices 2 and 3 of the Sox2 HMG domain (R74P and L97P, respectively), which in the pulldown assays of the present work were revealed to have a role in the interaction with the Otx2 protein ( Fig.…”

Section: Missense Mutations Identified In the Sox2 Hmg Domain Affect mentioning

confidence: 54%

Molecular links among the causative genes for ocular malformation: Otx2 and Sox2 coregulate Rax expression

Danno

Michiue

Hitachi

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

100

112

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The neural-related genes Sox2, Pax6, Otx2, and Rax have been associated with severe ocular malformations such as anophthalmia and microphthalmia, but it remains unclear as to how these genes are linked functionally. We analyzed the upstream signaling of Xenopus Rax (also known as Rx1) and identified the Otx2 and Sox2 proteins as direct upstream regulators of Rax. We revealed that endogenous Otx2 and Sox2 proteins bound to the conserved noncoding sequence (CNS1) located Ϸ2 kb upstream of the Rax promoter. This sequence is conserved among vertebrates and is required for potent transcriptional activity. Reporter assays showed that Otx2 and Sox2 synergistically activated transcription via CNS1. Furthermore, the Otx2 and Sox2 proteins physically interacted with each other, and this interaction was affected by the Sox2-missense mutations identified in these ocular disorders. These results demonstrate that the direct interaction and interdependence between the Otx2 and Sox2 proteins coordinate Rax expression in eye development, providing molecular linkages among the genes responsible for ocular malformation.anophthalmia ͉ comparative genomics ͉ microphthalmia ͉ rx1 ͉ Xenopus

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Section: Missense Mutations Identified In the Sox2 Hmg Domain Affect mentioning

confidence: 54%

Molecular links among the causative genes for ocular malformation: Otx2 and Sox2 coregulate Rax expression

Danno

Michiue

Hitachi

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

100

112

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“…8 One frameshift mutation causing continued translation beyond the normal stop codon, and three missense mutations in the HMG domain have also been reported and all are associated with anophthalmia or severe microphthalmia. 9,11,13 In this family, one patient has bilateral typical optic fissure closure defects (Figure 1, III.1) and two patients have iris anomalies indicating a minor form of optic fissure closure abnormality (Figure 1, II.1 and II.9). Typical optic fissure closure defects are not usually associated with SOX2 mutations.…”

Section: Discussionmentioning

confidence: 91%

Novel SOX2 partner-factor domain mutation in a four-generation family

et al. 2009

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Anophthalmia (no eye), microphthalmia (small eye) and associated ocular developmental anomalies cause significant visual handicap. In most cases the underlying genetic cause is unknown, but mutations in some genes, such as SOX2, cause ocular developmental defects, particularly anophthalmia, in a subset of patients. Here, we describe a four-generation family with a p.Asp123Gly mutation in the highly conserved partner-factor interaction region of the SOX2 protein, which is important for cell-specific actions of SOX2. The proband in this family has bilateral anophthalmia and several other family members have milder ocular phenotypes, including typical optic fissure coloboma. Expression studies indicate that Sox2 is expressed in the eye at the site of closure of the optic fissure during development. The SOX2 mutation in this family implicates the partner-factor interaction region of SOX2 in contributing to the specificity of SOX2 action in optic fissure closure. Our findings indicate that investigation of SOX2 in a broad range of eye anomaly patients aids in the determination of particular functions of SOX2 in development.

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“…A karyotype revealed a 4q inversion, which was not found in his parents. The breakpoints and a possible deletion region seen on karyotyping were difficult to define and were reported as 46,XY,der(4)?del (4) makes recurrence risk prediction difficult even when an underlying mutation is identified in SOX2, OTX2 or BMP4 (Bakrania et al, 2008;Faivre et al, 2006;Ragge et al, 2005b).…”

Section: Figurementioning

confidence: 99%

Chromosomal Rearrangements and Novel Genes in Disorders of Eye Development, Cataract and Glaucoma

et al. 2008

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Disorders of eye development such as microphthalmia and anophthalmia (small and absent eyes respectively), anterior segment dysgenesis where there may be pupillary and iris anomalies, and associated cataract and glaucoma, often lead to visual impairment or blindness. Currently treatment options are limited, as much is unknown about the molecular pathways that control normal eye development and induce the aberrant processes that lead to ocular defects. Mutation detection rates in most of the known genes are generally low, emphasizing the genetic heterogeneity of developmental ocular defects. Identification of the disease genes in these conditions improves the clinical information available for affected individuals and families, and provides new insights into the underlying biological processes for facilitation of better treatment options. Investigation of chromosomal rearrangements associated with an ocular phenotype has been especially powerful for disease gene identification. Molecular characterization of such rearrangements, which pinpoints the region by physically disrupting the causative gene or its regulatory sequences, allows for rapid elucidation of underlying genetic factors that contribute to the phenotype. Genes including PAX6, PITX2, FOXC1, MAF, TMEM114, SOX2, OTX2 and BMP4 have been identified in this way to be associated with developmental eye disorders. More recently, new methods in chromosomal analysis such as comparative genomic hybridization (CGH) microarray, have also enhanced our ability in disease gene identification.

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Recurrence of SOX2 anophthalmia syndrome with gonosomal mosaicism in a phenotypically normal mother

Cited by 53 publications

References 7 publications

Molecular links among the causative genes for ocular malformation: Otx2 and Sox2 coregulate Rax expression

Molecular links among the causative genes for ocular malformation: Otx2 and Sox2 coregulate Rax expression

Novel SOX2 partner-factor domain mutation in a four-generation family

Chromosomal Rearrangements and Novel Genes in Disorders of Eye Development, Cataract and Glaucoma

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