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

Nicolas Chassaing 1, 2, 3 Erica E. Davis Kelly L. Mcknight Adrienne R. Niederriter Alexandre Causse 2, 1 Véronique David 4, 5 Annaick Desmaison 6 Sophie Lamarre 7 Catherine Vincent-Delorme 8 Laurent Pasquier 9 Christine Coubes 10 Didier Lacombe 11 Massimiliano Rossi 12 Jean-Louis Dufier 13 Hélène Dollfus 14 Josseline Kaplan 15, 16 Nicholas Katsanis 17 Heather C. Etchevers Stanislas Faguer 18, 19, 20 Patrick Calvas 1, 2, 3
1 Hôpital Purpan [Toulouse]
2 UT3 - Université Toulouse III - Paul Sabatier
3 UDEAR - Unité différenciation épidermique et auto-immunité rhumatoïde
4 IGDR - Institut de Génétique et Développement de Rennes
5 Service de biologie moléculaire
6 ITAV - Institut des Technologies Avancées en sciences du Vivant
7 LISBP - Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés
8 Centre de Maladies Rares
9 CHU Pontchaillou [Rennes]
10 Service de Génétique Clinique
11 Service de génétique médicale
12 CRNL - Centre de recherche en neurosciences de Lyon
13 Service d'ophtalmologie [CHU Necker]
14 Centre de Référence pour les Affections Rares en Génétique Ophtalmologique (CARGO) et Service de Génétique Médicale
15 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
16 UPD5 - Université Paris Descartes - Paris 5
17 Center for Human Disease Modeling
18 Département de Néphrologie et Transplantation d'organes
Hôpital de Rangueil
19 Centre de référence des maladies rénales rares
20 I2MC - Institut des Maladies Métaboliques et Cardiovasculaires
Abstract : 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 high-throughput 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 mutant, we show physiologically relevant phenotypes altering SHH signaling and eye development upon abrogation of ptch1 in zebrafish 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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https://hal-univ-rennes1.archives-ouvertes.fr/hal-01282340
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Submitted on : Thursday, October 4, 2018 - 4:45:00 PM
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UNIV-RENNES1 | UNIV-ST-ETIENNE | USPC | INSA-TOULOUSE | UNIV-LYON1 | UNIV-RENNES | UR1-UFR-SVE | INRA | CNRS | IGDR | UNIV-PARIS5 | BIOSIT | INSA-GROUPE | UNIV-TLSE3 | UDL | TBI | TBI-I2M | INRAE | UNIV-PARIS | UP-SANTE

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Nicolas Chassaing, Erica E. Davis, Kelly L. Mcknight, Adrienne R. Niederriter, Alexandre Causse, et al.. Targeted resequencing identifies PTCH1 as a major contributor to ocular developmental anomalies and extends the SOX2 regulatory network. Genome Research, Cold Spring Harbor Laboratory Press, 2016, 26 (4), pp.474-485. ⟨10.1101/gr.196048.115⟩. ⟨hal-01282340⟩

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