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Syndromic chorioretinal coloboma associated with heterozygous de novo RARA mutation affecting an amino acid critical for retinoic acid interaction
Author(s) -
JakubiukTomaszuk Anna,
Murcia Pienkowski Victor,
Zietkiewicz Szymon,
Rydzanicz Małgorzata,
Kosińska Joanna,
Stawiński Piotr,
Szumiński Michał,
Płoski Rafał
Publication year - 2019
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.13611
Subject(s) - microphthalmia , biology , retinoic acid , coloboma , nonsense mutation , genetics , compound heterozygosity , microbiology and biotechnology , mutation , missense mutation , gene
Abstract 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.