Syndromic chorioretinal coloboma associated with heterozygous de novo RARA mutation affecting an amino acid critical for retinoic acid interaction.

Publisher: Munksgaard Country of Publication: Denmark NLM ID: 0253664 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1399-0004 (Electronic) Linking ISSN: 00099163 NLM ISO Abbreviation: Clin Genet Subsets: MEDLINE

Original Publication: Copenhagen, Munksgaard.

Heterozygote* ; Mutation*; Amino Acids/*metabolism ; Coloboma/*genetics ; Coloboma/*metabolism ; Retinoic Acid Receptor alpha/*genetics ; Tretinoin/*metabolism; Child ; Coloboma/diagnosis ; Genetic Association Studies ; Genetic Predisposition to Disease ; Humans ; Models, Molecular ; Pedigree ; Phenotype ; Retinoic Acid Receptor alpha/chemistry ; Structure-Activity Relationship

Retinoid acid receptors (RAR) are transcription factors that bind retinoic acid (RA), a metabolite of vitamin A. RARs are composed of three subunits encoded by RARA, RARB and RARG. In humans, RARB defects cause syndromic microphthalmia. So far, no germline pathogenic variants have been identified in RARA or RARG. We describe a girl with a de novo mutation NM_000964 c.826C > T (p.Arg276Trp) in RARA with symptoms overlapping those described in RARB patients (coloboma, muscular hypotonia, dilated pulmonary artery, ectopic kidney). RARA Arg276 residue is functionally important, as it was previously shown that its substitution for Ala or Gln causes a 50- or 21-fold impairment of RA binding, respectively. Moreover, in leukemic cells, the p.Arg611Trp mutation in a chimeric PML/RARA gene (corresponding to the RARA p.Arg276Trp detected in our patient) conferred resistance to therapy by decreasing binding of all-trans RA. The functional effect of RARA p.Arg276Trp was further confirmed by in silico modeling which showed that binding of RA by the Trp276 variant was similarly defective as in the deleterious model Ala276 mutant. We propose that RARA p.Arg276Trp causes the disease by affecting RA interaction with the RARA receptor.
(© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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Keywords: RARA; RARB; de novo mutation; retinoic acid receptors; syndromic coloboma; whole-exome sequencing

0 (Amino Acids)
0 (RARA protein, human)
0 (Retinoic Acid Receptor alpha)
5688UTC01R (Tretinoin)

Date Created: 20190726 Date Completed: 20200903 Latest Revision: 20200903

20231215

10.1111/cge.13611

31343737