Recessive and dominant mutations in retinoic acid receptor beta in cases with microphthalmia and diaphragmatic hernia.

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.

• 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)
• 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

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)