Recessive and Dominant Mutations in Retinoic Acid Receptor Beta in Cases with Microphthalmia and Diaphragmatic Hernia

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• 作者：Myriam Srour ; David Chitayat ; V¨¦ronique Caron ; Nicolas Chassaing ; Pierre Bitoun ; Lysanne Patry ; Marie-Pierre Cordier ; Jos¨¦-Mario Capo-Chichi ; Christine Francannet ; Patrick Calvas ; Nicola Ragge ; Sylvia Dobrzeniecka ; Fadi?F. Hamdan ; Guy?A. Rouleau ; Andr¨¦ Tremblay ; Jacques?L. Michaud
• 刊名：The American Journal of Human Genetics
• 出版年：2013
• 出版时间：3 October, 2013
• 年：2013
• 卷：93
• 期：4
• 页码：765-772
• 全文大小：834 K

文摘

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.