Recessive and dominant mutations in retinoic acid receptor beta in cases with microphthalmia and diaphragmatic hernia.
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.
Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal, QC H3T1C5, Canada.
Myriam
M
Srour
David
D
Chitayat
Véronique
V
Caron
Nicolas
N
Chassaing
Pierre
P
Bitoun
Lysanne
L
Patry
Marie-Pierre
MP
Cordier
José-Mario
JM
Capo-Chichi
Christine
C
Francannet
Patrick
P
Calvas
Nicola
N
Ragge
Sylvia
S
Dobrzeniecka
Fadi F
FF
Hamdan
Guy A
GA
Rouleau
André
A
Tremblay
Jacques L
JL
Michaud
D000293:Adolescent; D000853:Anophthalmos / Q000235:genetics / Q000378:metabolism; D059472:Exome; D005260:Female; D006548:Hernia, Diaphragmatic / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008850:Microphthalmos / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D018168:Receptors, Retinoic Acid / Q000235:genetics* / Q000378:metabolism; D012177:Retinol-Binding Proteins / Q000235:genetics / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism
D018168:Receptors, Retinoic Acid; D012177:Retinol-Binding Proteins; C082925:retinoic acid receptor beta; D014212:Tretinoin