Abstract |
Anophthalmia and/or microphthalmia, pulmonary hypoplasia, diaphragmatic hernia, and cardiac defects are the main features of PDAC syndrome. Recessive mutations in STRA6, encoding a membrane receptor for the retinol-binding protein, have been identified in some cases with PDAC syndrome, although many cases have remained unexplained. Using whole-exome sequencing, we found that two PDAC-syndrome-affected siblings, but not their unaffected sibling, were compound heterozygous for nonsense (c.355C>T [p.Arg119(∗)]) and frameshift (c.1201_1202insCT [p.Ile403Serfs(∗)15]) mutations in retinoic acid receptor beta (RARB). Transfection studies showed that p.Arg119(∗) and p.Ile403Serfs(∗)15 altered RARB had no transcriptional activity in response to ligands, confirming that the mutations induced a loss of function. We then sequenced RARB in 15 subjects with anophthalmia and/or microphthalmia and at least one other feature of PDAC syndrome. Surprisingly, three unrelated subjects with microphthalmia and diaphragmatic hernia showed de novo missense mutations affecting the same codon; two of the subjects had the c.1159C>T (Arg387Cys) mutation, whereas the other one carried the c.1159C>A (p.Arg387Ser) mutation. We found that compared to the wild-type receptor, p.Arg387Ser and p.Arg387Cys altered RARB induced a 2- to 3-fold increase in transcriptional activity in response to retinoic acid ligands, suggesting a gain-of-function mechanism. Our study thus suggests that both recessive and dominant mutations in RARB cause anophthalmia and/or microphthalmia and diaphragmatic hernia, providing further evidence of the crucial role of the retinoic acid pathway during eye development and organogenesis.
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Authors | Myriam Srour, David Chitayat, Véronique Caron, Nicolas Chassaing, Pierre Bitoun, Lysanne Patry, Marie-Pierre Cordier, José-Mario Capo-Chichi, Christine Francannet, Patrick Calvas, Nicola Ragge, Sylvia Dobrzeniecka, Fadi F Hamdan, Guy A Rouleau, André Tremblay, Jacques L Michaud |
Journal | American journal of human genetics
(Am J Hum Genet)
Vol. 93
Issue 4
Pg. 765-72
(Oct 03 2013)
ISSN: 1537-6605 [Electronic] United States |
PMID | 24075189
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved. |
Chemical References |
- Receptors, Retinoic Acid
- Retinol-Binding Proteins
- retinoic acid receptor beta
- Tretinoin
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Topics |
- Adolescent
- Anophthalmos
(genetics, metabolism)
- Exome
- Female
- Hernia, Diaphragmatic
(genetics, metabolism)
- Humans
- Infant, Newborn
- Male
- Microphthalmos
(genetics, metabolism)
- Mutation
- Receptors, Retinoic Acid
(genetics, metabolism)
- Retinol-Binding Proteins
(genetics, metabolism)
- Tretinoin
(metabolism)
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