Anophthalmia‐esophageal atresia syndrome caused by an <i>SOX2</i> gene deletion in monozygotic twin brothers with markedly discordant phenotypes

Zenteno, Juan Carlos; Pérez-Cano, Héctor Javier; Aguinaga, Mónica

doi:10.1002/ajmg.a.31384

Cited by 43 publications

(60 citation statements)

References 32 publications

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“…Our investigation for mutations in OTX2, PAX6, RAX and CHX10 in the more severely affected individuals in this pedigree did not reveal any contributory pathogenic mutations. The discordant findings in the ocular phenotypes of monozygotic twins with a c.70del20 SOX2 mutation 22 indicate that environmental or epigenetic factors may be contributing to the variable penetrance and expressivity associated with SOX2 mutations.…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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

et al. 2009

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“…(2) Phenotypic discordance in miscellaneous syndromes and diseases. A wide variety of conditions has been described in which there are examples of phenotypic discordance within MZ twin pairs, including: Proteus syndrome, male [Biesecker et al, 1998;Brockmann et al, 2008]; tibial aplasia with ectrodactyly, female [Dayer et al, 2007]; lymphedema-distichiasis [Kumar et al, 2007]; microphthalmia, syndromic 3, male [Zenteno et al, 2006]; Melnick-Needles syndrome, female [Robertson et al, 2006]; Klippel-Feil syndrome, female [Toyoshima et al, 2006]; Klippel-Trenaunay syndrome, male [Hofer et al, 2005]; frontonasal dysplasia, five discordant pairs [Mohammed et al, 2004]; Alagille syndrome 1 [Kamath et al, 2002]; Leopard syndrome 1 [Rudolph et al, 2001]; Fryns syndrome [Vargas et al, 2000]; Joubert syndrome, female [Raynes et al, 1999]; orofaciodigital syndrome 1, female [Shotelersuk et al, 1999]; trichorhinophalangeal syndrome 1, female [Naselli et al, 1998]; Sotos syndrome [Brown et al, 1998]; Aicardi syndrome, female [Costa et al, 1997] Table IV [Sommer et al, 2002]. Twelve pairs were concordantly right-handed (RH/ RH) and 13 pairs were discordantly handed, that is, right-handed/nonright-handed (RH/NRH).…”

Section: Other Examples Of Discordancementioning

confidence: 99%

Non‐identical monozygotic twins, intermediate twin types, zygosity testing, and the non‐random nature of monozygotic twinning: A review

Machin

2009

American J of Med Genetics Pt C

137

102

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Monozygotic twins (MZ) are rarely absolutely “identical.” This review discusses the types of genetic/epigenetic and prenatal environmental post‐zygotic mechanisms that cause discordance within such twin pairs. Some of these mechanisms—ranging from heterokaryotypia to skewed X‐chromosome inactivation—may cause extreme discordance, but these extremes are merely the more emphatic examples of discordance that, to some degree, underlies the majority of MZ twin pairs. Because of the entrenched misconception that MZ twins are necessarily identical, many MZ twin pairs are mistakenly designated as dizygotic (DZ). Clinical benefits to accurate zygosity determination include correct solid organ transplantation matching, if one twin requires donation for a non‐genetically mediated disease; the opportunity of preventive management for disorders that do not manifest synchronously; and better counseling to parents regarding their individually unique, and often psychologically puzzling, twin offspring. In twin pairs with complex and confusing biological origins, more detailed zygosity testing may be required. For example, intermediate trigametic and tetragametic chimeric dizygotic twins are reviewed, some of whom are, nevertheless, monochorionic (MC). Because of inter‐fetal vascular anastomoses in MC twins, genetic results from blood samples may not accurately reflect discordance in solid organs. Previously, it was thought that MZ twinning was some sort of embryological fluke. However, familial monozygotic twinning is more common than suggested by the literature. Seven new families are presented in an accompanying paper. Despite the difficulties and dangers of twin pregnancy (especially so for MC twins), human twinning persists, and continues to both challenge and fascinate parents, clinicians and geneticists. © 2009 Wiley‐Liss, Inc.

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“…Conditional deletion of Sox2 in the developing mouse retina results in the loss of competence to undergo neuronal differentiation, and mice that are hypomorphic for Sox2 exhibit reduced eye size (Taranova et al, 2006). Moreover, ~10% of human individuals with anophthalmia (lack of eye) or severe microphthalmia (small eye) carry a SOX2 mutation (Fantes et al, 2003;Hagstrom et al, 2005;Hanson and Van Heyningen, 1995;Ragge et al, 2005a;Ragge et al, 2005b;Zenteno et al, 2005;Zenteno et al, 2006) (for a review, see Hever et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Combinatorial regulation of optic cup progenitor cell fate by SOX2 and PAX6

2011

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SUMMARYIn humans, haploinsufficiency of either SOX2 or PAX6 is associated with microphthalmia, anophthalmia or aniridia. In this study, through the genetic spatiotemporal specific ablation of SOX2 on both wild-type and Pax6-haploinsufficent backgrounds in the mouse, we have uncovered a transcriptionally distinct and developmentally transient stage of eye development. We show that genetic ablation of SOX2 in the optic cup results in complete loss of neural competence and eventual cell fate conversion to nonneurogenic ciliary epithelium. This cell fate conversion is associated with a striking increase in PAX6, and genetically ablating SOX2 on a Pax6-haploinsufficient background partially rescues the Sox2-mutant phenotype. Collectively, these results demonstrate that precise regulation of the ratio of SOX2 to PAX6 is necessary to ensure accurate progenitor cell specification, and place SOX2 as a decisive factor of neural competence in the retina.

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Anophthalmia‐esophageal atresia syndrome caused by an SOX2 gene deletion in monozygotic twin brothers with markedly discordant phenotypes

Cited by 43 publications

References 32 publications

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

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

Non‐identical monozygotic twins, intermediate twin types, zygosity testing, and the non‐random nature of monozygotic twinning: A review

Combinatorial regulation of optic cup progenitor cell fate by SOX2 and PAX6

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