Sonic hedgehog mutations are an uncommon cause of developmental eye anomalies

Bakrania, Preeti; İşeri, Sibel Aylin Uğur; Wyatt, Alexander W.; Bunyan, Dave; Lam, Wayne; Salt, Alison; Ramsay, Jacqueline; Robinson, David; Ragge, Nicola

doi:10.1002/ajmg.a.33239

Cited by 33 publications

(23 citation statements)

References 20 publications

(28 reference statements)

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“…Such a myriad of ocular phenotypes has already been associated with mutations in most of the genes involved in ODA (Slavotinek 2011), especially genes involved in the SHH pathway such as SHH, GLI2, and PTCH1 (Roessler et al 2003;Ragge et al 2005b;Bakrania et al 2010). The wide phenotypic spectrum within our ODA cohort, coupled to the incomplete penetrance observed among families, suggests that additional factors contribute to the phenotype.…”

Section: Discussionmentioning

confidence: 83%

Targeted resequencing identifies PTCH1 as a major contributor to ocular developmental anomalies and extends the SOX2 regulatory network

et al. 2016

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Ocular developmental anomalies (ODA) such as anophthalmia/microphthalmia (AM) or anterior segment dysgenesis (ASD) have an estimated combined prevalence of 3.7 in 10,000 births. Mutations in SOX2 are the most frequent contributors to severe ODA, yet account for a minority of the genetic drivers. To identify novel ODA loci, we conducted targeted highthroughput sequencing of 407 candidate genes in an initial cohort of 22 sporadic ODA patients. Patched 1 (PTCH1), an inhibitor of sonic hedgehog (SHH) signaling, harbored an enrichment of rare heterozygous variants in comparison to either controls, or to the other candidate genes (four missense and one frameshift); targeted resequencing of PTCH1 in a second cohort of 48 ODA patients identified two additional rare nonsynonymous changes. Using multiple transient models and a CRISPR/Cas9-generated mutant, we show physiologically relevant phenotypes altering SHH signaling and eye development upon abrogation of ptch1 in zebrafish for which in vivo complementation assays using these models showed that all six patient missense mutations affect SHH signaling. Finally, through transcriptomic and ChIP analyses, we show that SOX2 binds to an intronic domain of the PTCH1 locus to regulate PTCH1 expression, findings that were validated both in vitro and in vivo. Together, these results demonstrate that PTCH1 mutations contribute to as much as 10% of ODA, identify the SHH signaling pathway as a novel effector of SOX2 activity during human ocular development, and indicate that ODA is likely the result of overactive SHH signaling in humans harboring mutations in either PTCH1 or SOX2.

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Section: Discussionmentioning

confidence: 83%

Targeted resequencing identifies PTCH1 as a major contributor to ocular developmental anomalies and extends the SOX2 regulatory network

et al. 2016

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“…Once the optic cup has formed, intraretinal Hh signaling regulates the differentiation of retinal progenitor cells [3]. Given its central role in eye development, it is unsurprising that mutations in genes encoding Hh pathway ligands (SHH) or targets (PAX2, VAX1) are associated with congenital ocular malformations in humans [6]–[9]. However, these mutations account for only a minority of patients; for the majority of MAC cases, the molecular defect has yet to be identified.…”

Section: Introductionmentioning

confidence: 99%

Sox11 Is Required to Maintain Proper Levels of Hedgehog Signaling during Vertebrate Ocular Morphogenesis

et al. 2014

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Ocular coloboma is a sight-threatening malformation caused by failure of the choroid fissure to close during morphogenesis of the eye, and is frequently associated with additional anomalies, including microphthalmia and cataracts. Although Hedgehog signaling is known to play a critical role in choroid fissure closure, genetic regulation of this pathway remains poorly understood. Here, we show that the transcription factor Sox11 is required to maintain specific levels of Hedgehog signaling during ocular development. Sox11-deficient zebrafish embryos displayed delayed and abnormal lens formation, coloboma, and a specific reduction in rod photoreceptors, all of which could be rescued by treatment with the Hedgehog pathway inhibitor cyclopamine. We further demonstrate that the elevated Hedgehog signaling in Sox11-deficient zebrafish was caused by a large increase in shha transcription; indeed, suppressing Shha expression rescued the ocular phenotypes of sox11 morphants. Conversely, over-expression of sox11 induced cyclopia, a phenotype consistent with reduced levels of Sonic hedgehog. We screened DNA samples from 79 patients with microphthalmia, anophthalmia, or coloboma (MAC) and identified two novel heterozygous SOX11 variants in individuals with coloboma. In contrast to wild type human SOX11 mRNA, mRNA containing either variant failed to rescue the lens and coloboma phenotypes of Sox11-deficient zebrafish, and both exhibited significantly reduced transactivation ability in a luciferase reporter assay. Moreover, decreased gene dosage from a segmental deletion encompassing the SOX11 locus resulted in microphthalmia and related ocular phenotypes. Therefore, our study reveals a novel role for Sox11 in controlling Hedgehog signaling, and suggests that SOX11 variants contribute to pediatric eye disorders.

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“…Mutations in SHH were rare as a cause of isolated A/M and/or coloboma [94], although A/M can occur with holoprosencephaly caused by mutations in this gene [95]. One three-generation pedigree has also been published, in which a novel 24 bp deletion in SHH segregated with iris and uveoretinal colobomas [96].…”

Section: Introductionmentioning

confidence: 99%

Eye development genes and known syndromes

Slavotinek

2011

Molecular Genetics and Metabolism

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Anophthalmia and microphthalmia (A/M) are significant eye defects because they can have profound effects on visual acuity. A/M is associated with non-ocular abnormalities in an estimated 33–95% of cases and around 25% of patients have an underlying genetic syndrome that is diagnosable. Syndrome recognition is important for targeted molecular genetic testing, prognosis and for counseling regarding recurrence risks. This review provides clinical and molecular information for several of the commonest syndromes associated with A/M: Anophthalmia-Esophageal-Genital syndrome, caused by SOX2 mutations, Anophthalmia and pituitary abnormalities caused by OTX2 mutations, Matthew-Wood syndrome caused by STRA6 mutations, Oculocardiafaciodental syndrome and Lenz microphthalmia caused by BCOR mutations, Microphthalmia Linear Skin pigmentation syndrome caused by HCCS mutations, Anophthalmia, pituitary abnormalities, polysyndactyly caused by BMP4 mutations and Waardenburg anophthalmia caused by mutations in SMOC1. In addition, we briefly discuss the ocular and extraocular phenotypes associated with several other important eye developmental genes, including GDF6, VSX2, RAX, SHH, SIX6 and PAX6.

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Sonic hedgehog mutations are an uncommon cause of developmental eye anomalies

Cited by 33 publications

References 20 publications

Targeted resequencing identifies PTCH1 as a major contributor to ocular developmental anomalies and extends the SOX2 regulatory network

Targeted resequencing identifies PTCH1 as a major contributor to ocular developmental anomalies and extends the SOX2 regulatory network

Sox11 Is Required to Maintain Proper Levels of Hedgehog Signaling during Vertebrate Ocular Morphogenesis

Eye development genes and known syndromes

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