The mutation spectrum of the bestrophin protein – functional implications |
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Authors: | B Bakall Towa Marknell Sofie Ingvast Markus J Koisti Ola Sandgren Wen Li Arthur A B Bergen Sten Andreasson Tomas Rosenberg Konstantin Petrukhin Claes Wadelius |
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Institution: | (1) Unit of Clinical Genetics, Department of Genetics and Pathology, University Hospital, S-751 85 Uppsala, Sweden e-mail: benjamin.bakall@klingen.uu.se, e-mail: claes.wadelius@klingen.uu.se, SE;(2) Department of Ophthalmology, University Hospital, S-901 85 Umea, Sweden, SE;(3) Department of Human Genetics, Merck Research Laboratories, West Point, PA 19486, USA, US;(4) The Netherlands Ophthalmic Research Institute, Postbox 12141, 1100 AC Amsterdam, The Netherlands, NL;(5) Department of Ophthalmology, University Hospital, S-221 85 Lund, Sweden, SE;(6) National Eye Clinic for the Visually Impaired, 1 Rymarksvej, DK-2900 Hellerup, Denmark, DK |
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Abstract: | Best’s macular dystrophy (BMD), also known as vitelliform macular degeneration type 2 (VMD2; OMIM 153700), is an autosomal
dominant form of macular degeneration with mainly juvenile onset. BMD is characterized by the accumulation of lipofuscin within
and beneath the retinal pigment epithelium. The gene causing the disease has been localized to 11q13 by recombination breakpoint
mapping. Recently, we have identified the causative gene encoding a protein named bestrophin, and mutations have been found
mainly to affect residues that are conserved from a family of genes in Caenorhabditis elegans. The function of bestrophin is so far unknown, and no reliable predictions can be made from sequence comparisons. We have
investigated the bestrophin gene in 14 unrelated Swedish, Dutch, Danish, and Moroccan families affected with BMD and found
eight new mutations. Including the previously published mutations, 15 different missense mutations have now been detected
in 19 of the 22 families with BMD investigated by our laboratory. Interestingly, the mutations cluster in certain regions,
and no nonsense mutations or mutations causing frame-shifts have been identified. Computer simulations of the structural elements
in the bestrophin protein show that this protein is probably membrane bound, with four putative transmembrane regions.
Received: 16 November 1998 / Accepted: 17 March 1999 |
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