A synonymous codon variant in two patients with autosomal recessive bestrophinopathy alters in vitro splicing of BEST1

Autosomal recessive bestrophinopathy (ARB) is a newly defined retinal dystrophy caused by biallelic mutations in bestrophin-1 (BEST1) and is hypothesized to represent the null bestrophin-1 phenotype in humans. The aim was to determine whether a synonymous BEST1 variant, c.102C>T, identified in tw...

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Bibliographic Details
Published in:Molecular vision 2010-12, Vol.16, p.2916-2922
Main Authors: Davidson, Alice E, Sergouniotis, Panagiotis I, Burgess-Mullan, Rosemary, Hart-Holden, Nichola, Low, Sancy, Foster, Paul J, Manson, Forbes D C, Black, Graeme C M, Webster, Andrew R
Format: Article
Language:English
Subjects:
Adult
alpha-Globins - genetics
Bestrophins
Child
Chloride Channels - genetics
Codon - genetics
Computational Biology
Eye Proteins - genetics
Female
Fibronectins - chemistry
Fibronectins - genetics
Fluorescence
Fundus Oculi
Genes, Recessive - genetics
HEK293 Cells
Humans
Male
Middle Aged
Mutation - genetics
Protein Structure, Tertiary
Retinal Dystrophies - genetics
RNA Splicing - genetics
Young Adult
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Summary:Autosomal recessive bestrophinopathy (ARB) is a newly defined retinal dystrophy caused by biallelic mutations in bestrophin-1 (BEST1) and is hypothesized to represent the null bestrophin-1 phenotype in humans. The aim was to determine whether a synonymous BEST1 variant, c.102C>T, identified in two unrelated ARB patients, alters pre-mRNA splicing of the gene. Additionally a detailed phenotypic characterization of this distinctive condition is presented for both patients. BEST1 was analyzed by direct sequencing. Patients underwent standard ophthalmic assessment. In silico and in vitro analysis using a minigene system was performed to assess whether a synonymous variant identified, c.102C>T p.Gly34Gly, alters pre-mRNA splicing of BEST1. Both ARB patients harbored either proven (patient 1; c.102C>T p.Gly34Gly and c.572T>C p.Leu191Pro) or presumed (patient 2; c.102C>T p.Gly34Gly and c.1470_1471delCA, p.His490GlnfsX24) biallelic mutations in BEST1 and were found to have phenotypes consistent with ARB. In vitro analysis of the synonymous variant, c.102C>T p.Gly34Gly, demonstrated it to introduce a cryptic splice donor site 52 nucleotides upstream of the actual splice donor site. The novel BEST1 variant identified, c.102C>T p.Gly34Gly, alters pre-mRNA splicing in vitro and is potentially pathogenic. In vivo this splicing variant is predicted to lead to the production of an mRNA transcript with a premature termination codon (p.Glu35TrpfsX11) that is predicted to be degraded by NMD.
ISSN:1090-0535
1090-0535