Detailed analysis of family with autosomal recessive bestrophinopathy associated with new BEST1 mutation

Abstract

PurposeTo describe the clinical and genetic findings in a patient with autosomal recessive bestrophinopathy (ARB) and his healthy parents.MethodsThe patient and his healthy non-consanguineous parents underwent detailed ophthalmic evaluations including electro-oculography (EOG), spectral-domain optical coherence tomography (SD-OCT), and fundus autofluorescence (FAF) imaging. Mutation analysis of the BEST1 gene was performed by Sanger sequencing.ResultsThe FAF images showed multiple spots of increased autofluorescence, and the sites of these spots corresponded to the yellowish deposits detected by ophthalmoscopy. SD-OCT showed cystoid macular changes and a shallow serous macular detachment. The Arden ratio of the EOG was markedly reduced to 1.1 in both eyes. Genetic analysis of the proband detected two sequence variants of the BEST1 gene in the heterozygous state: a novel variant c.717delG, p.V239VfsX2 and an already described c.763C>T, p.R255W variant associated with Best vitelliform macular dystrophy and ARB. The proband’s father carried the c.717delG, p.V239VfsX2 variant in the heterozygous state, and the mother carried the c.763C>T, p.R255W variant in the heterozygous state. The parents who were heterozygous for the BEST1 variants had normal visual acuity, EOG, SD-OCT, and FAF images.ConclusionsIn a truncating BEST1 mutation, the phenotype associated with ARB is most likely due to a marked decrease in the expression of BEST1 promoted by the nonsense-mediated decay surveillance mechanism, and it may depend on the position of the premature termination of the codon created.

Screening of BEST1 Gene in a Chinese Cohort With Best Vitelliform Macular Dystrophy or Autosomal Recessive Bestrophinopathy

“…26 Two recent studies reported several Japanese patients carrying the mutation p.R255W, in either the compound heterozygous or the homozygous state. These patients showed a phenotype of ARB, 31,32 whereas their heterozygous parents were entirely normal, both clinically and electrophysiologically. 32 In the current study, seven patients with the mutation p.R255W (five in the compound heterozygous state and two in the heterozygous state) had a clearly ARB phenotype.…”

“…These patients showed a phenotype of ARB, 31,32 whereas their heterozygous parents were entirely normal, both clinically and electrophysiologically. 32 In the current study, seven patients with the mutation p.R255W (five in the compound heterozygous state and two in the heterozygous state) had a clearly ARB phenotype. Therefore, we speculated the mutation p.R255W might be a common recessive mutation for Asian patients.…”

“…The mutation p.A195V is one of the most prevalent mutations among those patients with biallelic mutations, 32 and the patients carrying the heterozygous mutation p.A195V compounded with another heterozygous mutation exhibited either a phenotype of BVMD or of ARB, whereas the individuals carrying the heterozygous mutation p.A195V alone did not shown any phenotype of BVMD or ARB. 15,23,32 In the current study, the mutation p.R25W was identified in two ARB patients in the compound heterozygous state (one coupled with a synonymous change c.763C>A and another one with a variant c.*24C>T). The father of proband 010397 carrying the mutation c.*24C>T was healthy, both clinically and electrophysiologically, whereas her mother, who harbored the mutation p.R25W, had an abnormal EOG (Fig.…”

Novel BEST1 gene mutations associated with two different forms of macular dystrophy in Tunisian families

“…BEST1 ( VMD2 ) is a gene located on chromosome 11 (11q12.3) that encodes for a 585 amino acid transmembrane channel protein called bestrophin 1 (or Best1), located in the retinal pigment epithelium (RPE) . Although the exact function of BEST1 is still not clear, it is generally believed to act as a chloride ion channel and possibly to have dual functions as a chloride channel and a regulator of Ca2 + channels in RPE cells .…”

Clinical and Genetic Findings of Autosomal Recessive Bestrophinopathy (ARB)

“…However, the frequency of this mutation is not really known in Caucasian patients and its frequency should be evaluated in larger groups. This mutation is one of the most prevalent mutations among patients with compound mutations and it is associated with either a BVMD or of ARB phenotype, whereas individuals carrying the mutation at a heterozygous state alone did not show any phenotypic features of BVMD or ARB [10][11][12]18,19].…”