Late-Onset Stargardt Disease Due to Mild, Deep-Intronic ABCA4 Alleles
| Autor: | Jan-Willem R. Pott, Galuh D.N. Astuti, Esmee H. Runhart, Christian Gilissen, Silvia Albert, Carel B. Hoyng, Stéphanie S. Cornelis, Dyon Valkenburg, Joke B. G. M. Verheij, Riccardo Sangermano, Ellen A.W. Blokland, Mubeen Khan, Frans P.M. Cremers, L. Ingeborgh van den Born, Nathalie M. Bax |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty PENETRANCE Population Visual Acuity ABCA4 P.ASN1868ILE ALLELE Late onset Kaplan-Meier Estimate Biology Gastroenterology disease expression Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] NONPENETRANCE 03 medical and health sciences All institutes and research themes of the Radboud University Medical Center 0302 clinical medicine Gene Frequency Internal medicine differential diagnosis medicine Humans Allele education Allele frequency Alleles Aged education.field_of_study Genetic Variation Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] MOUSE MODEL Middle Aged RETINAL-PIGMENT EPITHELIUM medicine.disease Penetrance AUTOFLUORESCENCE Stargardt disease 030104 developmental biology 030221 ophthalmology & optometry biology.protein ATP-Binding Cassette Transporters Female Age of onset |
| Zdroj: | Investigative Ophthalmology and Visual Science, 60, 4249-4256 Investigative Ophthalmology and Visual Science, 60, 13, pp. 4249-4256 Investigative ophthalmology & visual science, 60(13), 4249-4256. ASSOC RESEARCH VISION OPHTHALMOLOGY INC |
| ISSN: | 0146-0404 |
| Popis: | PURPOSE. To investigate the role of two deep-intronic ABCA4 variants, that showed a mild splice defect in vitro and can occur on the same allele as the low penetrant c.5603A>T, in Stargardt disease (STGD1).METHODS. Ophthalmic data were assessed of 18 STGD1 patients who harbored c.769-784C>T or c.4253+43G>A in combination with a severe ABCA4 variant. Subjects carrying c.[769784C>T; 5603A>T] were clinically compared with a STGD1 cohort previously published carrying c.5603A>T noncomplex. We calculated the penetrances of the intronic variants using ABCA4 allele frequency data of the general population and investigated the effect of c.769-784C>T on splicing in photoreceptor progenitor cells (PPCs).RESULTS. Mostly, late-onset, foveal-sparing STGD1 was observed among subjects harboring c.769-784C>T or c.4253+43G>A (median age of onset, 54.5 and 52.0 years, respectively). However, ages of onset, phenotypes in fundo, and visual acuity courses varied widely. No significant clinical differences were observed between the c.[769-784C>T; 5603A>T] cohort and the c.4253+43G>A or the c.5603A>T cohort. The penetrances of c.769-784C>T (20.5%-39.6%) and c.4253+43G>A (35.8%-43.1%) were reduced, when not considering the effect of yet unidentified or known factors in cis, such as c.5603A>T (identified in 7/7 probands with c.769-784C>T; 1/8 probands with c.4253+43G>A). Variant c.769-784C>T resulted in a pseudo-exon insertion in 15% of the total mRNA (i.e., similar to 30% of the c.769-784C>T allele alone).CONCLUSIONS. Two mild intronic ABCA4 variants could further explain missing heritability in late-onset STGD1, distinguishing it from AMD. The observed clinical variability and calculated reduced penetrance urge research into modifiers within and outside of the ABCA4 gene. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|