Regular ArticleBest's Vitelliform Dystrophy (VMD2) Maps between D11S903 and PYGM: No Evidence for Locus Heterogeneity
Abstract
Vitelliform macular dystrophy, also known as Best's disease (BD), is an autosomal dominant disorder typically characterized by an accumulation of yellowish material in the macular area. The disease is slowly progressive and eventually results in atrophy of the retinal pigment epithelium and photoreceptor cells, thus severely impairing central vision. The biochemical defect underlying this condition is unknown. More recently, the BD locus (VMD2) was mapped to chromosome 11 by genetic linkage to microsatellite markers at D11S871 and INT2. In the present study, we report a detailed genetic analysis in three multigeneration Best's disease families using eight microsatellite markers spanning approximately 26 cM around the putative BD locus. We demonstrate linkage between Best's disease and the markers used. Furthermore, haplotype analysis in our unrelated Best's disease families identified three distinct haplotypes associated with the disease, strongly suggesting independent origins of the BD mutation. Finally, we characterized two recombinant BD chromosomes that significantly refine the location of the disease gene to a 3.7-cM interval between markers at D11S903 and PYGM. PCR-hybrid mapping sublocalized this interval to the pericentromeric region of chromosome 11.
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Macular Dystrophies
2005, Retina: Fourth EditionOcular genetics: Current understanding
2004, Survey of OphthalmologyOver the past decade, there has been an exponential increase in our knowledge of heritable eye conditions. Coincidentally, our ability to provide accurate genetic diagnoses has allowed appropriate counseling to patients and families. A summary of our current understanding of ocular genetics will prove useful to clinicians, researchers, and students as an introduction to the subject.
Best vitelliform macular dystrophy (VMD2) is an autosomal dominant dystrophy with a juvenile age of onset. Mutations in the Bestrophin gene were shown in patients affected with VMD2. In a mutation study, we made three new and interesting observations. First, we identified possible mutation hotspots within the gene, suggesting that particular regions of the protein have greater functional significance than others. Second, we described a 2-bp deletion in a part of the gene where mutations have not previously been reported; this mutation causes a frameshift and subsequent premature termination of the protein. Finally, we have evidence that some mutations are associated with variable expression of the disease, suggesting the involvement of other factors or genes in the disease phenotype.
We have generated a transcript map of an approximately 1.2-Mb region from human chromosome band 11q13 between the lociVEGFBandCAPN1,which flank the multiple endocrine neoplasia type 1 (MEN 1) locus. In total, we isolated 144 cosmids from this region and generated a sequence-ready cosmid contig of the approximately 500-kb region between the neurexin locus and D11S2196E. We identified 54 genes/ESTs by sample sequencing and have constructed a transcript map of this region. Genes were found to be clustered in three regions, and one of these genes was identical to the recently identifiedMEN1locus. Relative to the latter, we have mapped the positions of 13 known genes, 18 genes which show homology to genes from humans or other organisms, and 22 genes/ESTs that appear novel. In addition, we have ascertained the directions of transcription of some of these genes and have determined intergenic distances between many loci. Full characterization of some of these genes, as well as the novel ESTs, will be useful in identifying candidate genes for other diseases known to map to this chromosomal region.
Tissue expression of a gene potentially implicated in some diseases involving the retina and the kidney
1997, Comptes Rendus de l'Academie des Sciences - Serie IIINous avons produit un anticorps monoclonal (HA34) qui révèle spécifiquement l'épithélium pigmentaire de l'œil et les tubes contournés proximaux du rein. L'épitope reconnu est présent dans ces deux organes quelle que soit l'étape du développement considérée. Cet épitope n'apparaît pas sur le rein des autres mammifères étudiés. Il appartient à une protéine complexe dont le poids moléculaire est d'environ 200 kDa. En contraste avec sa spécifité tissulaire, l'épitope reconnu par HA34 est présent de façon ubiquitaire sur les cellules cultivées in vitro, ce qui a permis d'utiliser la méthode des hybrides somatiques interspécifiques pour localiser le gène impliqué. Le gène a successivement été assigné au chromosome 11 puis dans la bande cytogénétique 1 1q13 entre les microsatellites D11S1777 (AFMaO46wa9) et D11S913 (AFM164zf12) dans un espace de 9 cM. Cette région est impliquée dans des rétinopathies pigmentaires dont certaines peuvent être associées à des anomalies du rein. Ces observations nous permettent de proposer ce gène comme candidat potentiel pour certaines de ces maladies.
We have produced a monoclonal antibody (HA34) that specifically reveals the pigmented epithelium in the eye and the proximal convoluted tubules of the kidney, whatever the developmental stage. The results obtained with the kidney of other mammals suggest that the antigen is human specific. Its molecular weight is approximately 200 kDa. The epitope recognized by HA34 is always present on cell lines grown in vitro. This allowed us to use somatic cell interspecific hybrids to localize the gene implicated in the cytogenetic band 11q13, between microsatellites D11S1777 (AFMa046wa9) and D11S913 (AFM164zf12) in a 9 cM space. This region is involved informs ofretinitispigmentosa, some of which can also include kidney abnormalities. We propose that this gene is possibly implicated in some of these diseases.
A sequence-ready high-resolution physical map of the best macular dystrophy gene region in 11q12-q13
1997, GenomicsBest disease, an autosomal dominant inherited macular degenerative disorder, was previously localized between D11S1765 and UGB (uteroglobin) in 11q13 by genetic linkage analysis. Since this region was found to be refractory to cloning in YAC (yeast artificial chromosome)-based vectors, a P1 artificial chromosome (PAC) contig was assembled. Gridded PAC libraries representing a 16-fold genome equivalent were screened by hybridization using PCR products representing STSs derived from YAC end sequences, markers binned to 11q13, and PAC-derived insert ends. A highly marker dense ∼1.7-Mb PAC contig that encompassed the disease gene region was constructed, allowing us to order accurately the markers throughout the region and to provide the most precise estimate of its physical size. Using this contig, thus far we have mapped seven anonymous ESTs and five known genes into this region. This high-resolution physical map will facilitate the isolation of polymorphic markers for refinement of the disease gene region, as well as the identification of candidate genes by exon trapping, cDNA selection, and gene prediction from PAC-derived genomic sequence.