BEST1 – Vitelliform Macular Dystrophy 2

BEST1 encodes bestrophin-1, a 585-amino-acid transmembrane protein localized to the basolateral membrane of the retinal pigment epithelium (RPE). Heterozygous variants in BEST1 cause autosomal dominant vitelliform macular dystrophy 2 (Best disease, MONDO:0007931), characterized by subretinal lipofuscin accumulation, geographic atrophy, and choroidal neovascularization.

In a cohort of 41 unrelated juvenile-onset Best disease probands, 23 distinct BEST1 mutations were identified, segregating with disease in multiple families. In parallel, 32 adult-onset vitelliform macular dystrophy (AVMD) patients harbored four BEST1 variants—two shared with Best disease—and no pathogenic variants were found in 200 age-related macular degeneration (AMD) cases (PMID:10854112).

The mutation spectrum is predominantly missense, clustering within the N-terminal half of bestrophin-1. A representative pathogenic change is c.81C>G (p.Ser27Arg) identified in Best disease (PMID:10854112). Sporadic cases further support causality: a de novo c.663C>G (p.Cys221Trp) substitution was detected in a singleton Best macular dystrophy patient (PMID:10682987).

Electrophysiological studies reveal that missense mutations such as c.879G>C (p.Gln293His) abolish Ca²⁺-activated Cl⁻ currents and exert a dominant-negative effect on co-expressed wild-type channels in HEK-293 cells (PMID:17287362).

Transcriptional analyses demonstrate that BEST1 promoter activity in RPE cells is driven by microphthalmia-associated transcription factor (MITF) and SOX family factors binding to proximal E-box elements, underlying the RPE-specific expression necessary for disease pathogenesis (PMID:14982938; PMID:20530484).

Although dominant-negative missense alleles predominate, rare frameshift and nonsense mutations leading to haploinsufficiency have been described, indicating that loss of function can also contribute to Best disease (PMID:14517959).

Collectively, strong genetic and moderate functional evidence establish BEST1 as the definitive cause of vitelliform macular dystrophy 2. BEST1 mutation screening is recommended for patients presenting with vitelliform lesions to inform diagnosis, prognosis, and genetic counseling.

References

• European Journal of Human Genetics • 2000 • Mutations in the VMD2 gene are associated with juvenile-onset vitelliform macular dystrophy (Best disease) and adult vitelliform macular dystrophy but not age-related macular degeneration. PMID:10854112
• American Journal of Ophthalmology • 2000 • A novel spontaneous missense mutation in VMD2 gene is a cause of a best macular dystrophy sporadic case. PMID:10682987
• Journal of Medical Genetics • 2007 • New VMD2 gene mutations identified in patients affected by Best vitelliform macular dystrophy. PMID:17287362
• The Journal of Biological Chemistry • 2004 • Analysis of the VMD2 promoter and implication of E-box binding factors in its regulation. PMID:14982938
• The Journal of Biological Chemistry • 2010 • SOX9, through interaction with microphthalmia-associated transcription factor (MITF) and OTX2, regulates BEST1 expression in the retinal pigment epithelium. PMID:20530484

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