The majority of disease-associated mutations in <i>BEST1</i> constitute missense mutations and were shown <i>in vitro</i> to lead to a reduction in mutant protein half-life causing Best disease (BD), a rare autosomal dominant macular dystrophy.
Here, we characterized six Best vitelliform macular dystrophy (BVMD)-associated BEST1 dominant mutations by documenting the patients' phenotypes, examining the subcellular localization of endogenous BEST1 and surface Ca<sup>2+</sup>-dependent Cl<sup>-</sup> currents in patient-derived RPEs, and analyzing the functional influences of these mutations on BEST1 in HEK293 cells.
Sanger sequencing of all exons of the BEST1 gene in both families identified two new mutations: a missense mutation c.C91A [p.L31 M] at the N-terminal transmembrane domain within the ARB family and a nonsense mutation C1550G (p.S517X) in the C-terminal domain segregating in the BVMD family.
Here, we have generated an induced pluripotent stem cell (iPSC) line derived from a Best disease patient carrying a new dominant mutation in the BEST1 gene.
Pathogenicity of new BEST1 variants identified in Italian patients with best vitelliform macular dystrophy assessed by computational structural biology.
Further, the inheritance pattern of BEST1 mutations in the families confirmed the diagnosis of ARB in probands in families A, B and C, while the inheritance of heterozygous BEST1 mutation in family D (p.Thr91Ile) was suggestive of BVMD.
Taken together, our data provide insight into the molecular pathways of dominantly and recessively acting BEST1 missense mutations suggesting that the site of subcellular protein quality control as well as the rate and degree of mutant protein degradation are ultimately responsible for the distinct retinal disease phenotypes in BD and ARB.
Covariates included either Fracture Risk Assessment Tool (FRAX) major osteoporotic fracture probability calculated with BMD (FRAX-BMD), or individual clinical risk factors (CRF) including age, total hip BMD, race, falls, and prevalent fracture after age 50 years.
The physiological and pathological significance of BEST1 is highlighted by the fact that over 200 distinct mutations in the BEST1 gene have been genetically linked to a spectrum of at least five retinal degenerative disorders, such as Best vitelliform macular dystrophy (Best disease).
One hundred thirteen patients were identified with likely disease-causing sequence variants in BEST1 (99 Best disease and 14 autosomal recessive bestrophinopathy).
These findings expand the spectrum of BEST1 genetic variation and will be valuable for genetic counseling and the development of therapeutic interventions for patients with BVMD.
To describe the presenting features and functional outcomes in a series of patients with choroidal neovascular membrane complicating BEST1-related retinopathy (Best disease and autosomal recessive bestrophinopathy).
Compared to baseline, BMD significantly increased for S-WEIGHT in the arms (+4%, P<0.001), legs (+8%, P<0.01), pelvis (+6%, P<0.01) and lumbar spine (+4%, P<0.05), whereas BMD did not significantly change for S-CORE at any site.
These salient alterations detected at the RPE apical domain in cBest as well as in BVMD- and ARB-hiPSC-RPE model systems provide novel insights into the pathological mechanism of BEST1-linked disorders that will allow for development of critical outcome measures guiding therapeutic strategies for bestrophinopathies.
The aim of the current study was to establish the BEST1 mutation spectrum in Chinese patients with BVMD and ARB and to describe the phenotypic characteristics of patients carrying BEST1 mutations.
In conclusion, BEST1 gene mutations and polymorphisms have been reported in diverse ethnic groups, and the present study identified a novel BEST1 gene mutation and an SNP that occurred simultaneously in a Chinese patient with BVMD.