Refined genetic localization of the Best disease gene in 11q13 and physical mapping of linked markers on radiation hybrids

Abstract

Best's macular dystrophy, also known as vitelliform macular degeneration type 2 (VMD-2), is an autosomal dominant eye disorder that causes reduced visual acuity. It generally manifests itself in the teenage years. The gene mutated in VMD-2 patients may provide valuable insight into the biological mechanisms of the far more common disorder age-related macular degeneration. The VMD-2 gene has been localized to 11q13 between UGB and Fc epsilon RI. In order to clone the gene positionally, a large Swedish VMD-2 family dating back to the 17th century was studied for recombinations. Since the last study, another 40 microsatellite markers have been analyzed in the family; the closest centromeric flanking marker, D11S4076, revealed two recombinations and the closest telomeric flanking marker, UGB, revealed one recombination. The recombinations have occurred in affected individuals, which eliminates the potential problem of reduced penetrance. The order and physical distance between 22 markers located at proximal 11q13 were analyzed on the G3 Stanford radiation-reduced cell hybrids. The data suggest that the VMD-2 region flanked by the microsatellite markers D11S4076 and UGB is approximately 980 kb.

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

“…6,15 Haplotypes were constructed where additional family members were available and segregation analysis of the disease-associated haplotype was performed (Table 1).…”

“…2,3 Ultimately, choroidal neovascularisation and/or chorioretinal atrophy occur and are generally associated with severe loss of visual acuity. Although exceptions have been reported, [4][5][6] electro-oculography (EOG) is thought to be typically abnormal in Best disease, providing an important diagnostic tool for carrier detection. 7,8 Both the ophthalmoscopic and electrodiagnostic features of Best disease suggest the RPE to be the primary site of the defect.…”

“…6,[11][12][13][14][15][16] Recently, the VMD2 gene was identified by positional cloning, and thus far 29 different disease-related mutations have been described. [17][18][19][20] VMD2 is RPE-specific and is comprised of 11 exons coding for a 585 amino acid protein of unknown function.…”

VMD2 mutations in vitelliform macular dystrophy (Best disease) and other maculopathies

“…It is possible that other genetic or environmental factors interact with VMD2 defects to produce the varying phenotype. This possibility is supported by the documentation of non-penetrance in two families [Weber et al, 1994;Graff et al, 1997]. Molecular study of the VMD2 gene may be useful, however, in the definition of the clinical phenotype of Best disease.…”

Best's macular dystrophy in Australia: phenotypic profile and identification of novel BEST1 mutations

“…Although the precise role of the encoded protein is still debated, bestrophin 1 is thought to belong to a family of calcium-activated chloride channels, [5][6][7][8] and has been identified on the basolateral plasma membrane of retinal pigment epithelium (RPE). [9][10][11][12] It is thought to be a separate disease entity to adult vitelliform macular dystrophy (AVMD), which is a rare disorder, with autosomal dominant inheritance, and variable penetrance and expressivity. Mutations in both the RDS and BEST1 genes are responsible for AVMD, and it is considered as a subset of pattern dystrophies.…”