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

Anna Jakubiuk‐Tomaszuk , Victor Murcia Pienkowski , Szymon Ziętkiewicz , Małgorzata Rydzanicz , Joanna Kosińska , Piotr Stawiński , Michał Szumiński , Rafał Płoski


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.
Author Anna Jakubiuk‐Tomaszuk
Anna Jakubiuk‐Tomaszuk,,
, Victor Murcia Pienkowski
Victor Murcia Pienkowski,,
, Szymon Ziętkiewicz (IFB / M020 / DMCB)
Szymon Ziętkiewicz,,
- Department of Molecular and Cellular Biology
, Małgorzata Rydzanicz
Małgorzata Rydzanicz,,
, Joanna Kosińska
Joanna Kosińska,,
, Piotr Stawiński
Piotr Stawiński,,
, Michał Szumiński
Michał Szumiński,,
, Rafał Płoski
Rafał Płoski,,
Journal seriesClinical Genetics, ISSN 0009-9163, (N/A 100 pkt)
Issue year2019
Publication size in sheets0.5
Keywords in Englishde novo mutation, RARA, RARB, retinoic acid receptors, syndromic coloboma, whole-exome sequencing
ASJC Classification2716 Genetics(clinical); 1311 Genetics
Languageen angielski
Score (nominal)100
Score sourcejournalList
ScoreMinisterial score = 100.0, 28-01-2020, ArticleFromJournal
Publication indicators Scopus SNIP (Source Normalised Impact per Paper): 2018 = 1.22; WoS Impact Factor: 2018 = 4.104 (2) - 2018=3.544 (5)
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