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

Am J Hum Genet. 2013 Oct 3;93(4):765-72. doi: 10.1016/j.ajhg.2013.08.014. Epub 2013 Sep 26.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Anophthalmos / genetics
  • Anophthalmos / metabolism
  • Exome
  • Female
  • Hernia, Diaphragmatic / genetics*
  • Hernia, Diaphragmatic / metabolism
  • Humans
  • Infant, Newborn
  • Male
  • Microphthalmos / genetics*
  • Microphthalmos / metabolism
  • Mutation*
  • Receptors, Retinoic Acid / genetics*
  • Receptors, Retinoic Acid / metabolism
  • Retinol-Binding Proteins / genetics
  • Retinol-Binding Proteins / metabolism
  • Tretinoin / metabolism

Substances

  • Receptors, Retinoic Acid
  • Retinol-Binding Proteins
  • retinoic acid receptor beta
  • Tretinoin