High-throughput custom capture sequencing identifies novel mutations in coloboma-associated genes: Mutation in DNA-binding domain of retinoic acid receptor beta affects nuclear localization causing ocular coloboma.

Autor: Kalaskar VK; Pediatric, Developmental & Genetic Ophthalmology Section, Ophthalmic Genetics and Visual Function Branch (OGVFB), National Eye Institute (NEI), National Institutes of Health (NIH), Bethesda, Maryland., Alur RP; Pediatric, Developmental & Genetic Ophthalmology Section, Ophthalmic Genetics and Visual Function Branch (OGVFB), National Eye Institute (NEI), National Institutes of Health (NIH), Bethesda, Maryland., Li LK; Pediatric, Developmental & Genetic Ophthalmology Section, Ophthalmic Genetics and Visual Function Branch (OGVFB), National Eye Institute (NEI), National Institutes of Health (NIH), Bethesda, Maryland., Thomas JW; National Institutes of Health Intramural Sequencing Center, National Human Genome Research Institute, NIH, Bethesda, Maryland., Sergeev YV; Protein Biochemistry and Molecular Modeling Group, OGVFB, NEI, NIH, Bethesda, Maryland., Blain D; Ophthalmic Clinical Genetics Section, OGVFB, NEI, NIH, Bethesda, Maryland., Hufnagel RB; Medical Genetics and Ophthalmic Genomics Unit, OGVFB, NEI, NIH, Bethesda, Maryland., Cogliati T; Pediatric, Developmental & Genetic Ophthalmology Section, Ophthalmic Genetics and Visual Function Branch (OGVFB), National Eye Institute (NEI), National Institutes of Health (NIH), Bethesda, Maryland., Brooks BP; Pediatric, Developmental & Genetic Ophthalmology Section, Ophthalmic Genetics and Visual Function Branch (OGVFB), National Eye Institute (NEI), National Institutes of Health (NIH), Bethesda, Maryland.; Ophthalmic Clinical Genetics Section, OGVFB, NEI, NIH, Bethesda, Maryland.
Jazyk: angličtina
Zdroj: Human mutation [Hum Mutat] 2020 Mar; Vol. 41 (3), pp. 678-695. Date of Electronic Publication: 2019 Dec 09.
DOI: 10.1002/humu.23954
Abstrakt: Uveal coloboma is a potentially blinding congenital ocular malformation caused by the failure of optic fissure closure during the fifth week of human gestation. We performed custom capture high-throughput screening of 38 known coloboma-associated genes in 66 families. Suspected causative novel variants were identified in TFAP2A and CHD7, as well as two previously reported variants of uncertain significance in RARB and BMP7. The variant in RARB, unlike previously reported disease mutations in the ligand-binding domain, was a missense change in the highly conserved DNA-binding domain predicted to affect the protein's DNA-binding ability. In vitro studies revealed lower steady-state protein levels, reduced transcriptional activity, and incomplete nuclear localization of the mutant RARB protein compared with wild-type. Zebrafish studies showed that human RARB messenger RNA partially reduced the ocular phenotype caused by morpholino knockdown of rarga gene, a zebrafish homolog of human RARB. Our study indicates that sequence alterations in known coloboma genes account for a small percentage of coloboma cases and that mutations in the RARB DNA-binding domain could result in human disease.
(© 2019 The Authors. Human Mutation Published by Wiley Periodicals, Inc.)
Databáze: MEDLINE
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