Missense Mutations in a Retinal Pigment Epithelium Protein, Bestrophin-1, Cause Retinitis Pigmentosa

Abstract

Bestrophin-1 is preferentially expressed at the basolateral membrane of the retinal pigmented epithelium (RPE) of the retina. Mutations in the BEST1 gene cause the retinal dystrophies vitelliform macular dystrophy, autosomal-dominant vitreochoroidopathy, and autosomal-recessive bestrophinopathy. Here, we describe four missense mutations in bestrophin-1, three that we believe are previously unreported, in patients diagnosed with autosomal-dominant and -recessive forms of retinitis pigmentosa (RP). The physiological function of bestrophin-1 remains poorly understood although its heterologous expression induces a Cl--specific current. We tested the effect of RP-causing variants on Cl- channel activity and cellular localization of bestrophin-1. Two (p.L140V and p.I205T) produced significantly decreased chloride-selective whole-cell currents in comparison to those of wild-type protein. In a model system of a polarized epithelium, two of three mutations (p.L140V and p.D228N) caused mislocalization of bestrophin-1 from the basolateral membrane to the cytoplasm. Mutations in bestrophin-1 are increasingly recognized as an important cause of inherited retinal dystrophy.

Frequency, Genotype, and Clinical Spectrum of Best Vitelliform Macular Dystrophy: Data From a National Center in Denmark

“…Autosomal recessive BEST1 mutations are usually associated with more severe retinal dystrophies, such as autosomal recessive bestrophinopathy (ARB) [1][2][3][4][5] and retinitis pigmentosa. 6 Best disease is considered a rare genetic disease, but the prevalence in still unknown. A previous estimate of its prevalence, carried out in Northern Sweden, arrived at 2 per 10,000.…”

Normal Electrooculography in Best Disease and Autosomal Recessive Bestrophinopathy

“…The clinical spectrum of disorders include (i) diseases predominantly affecting the macula -Best disease (BD) and Adult Vitelliform Macular Dystrophy (AVMD); (ii) generalised retinal involvement -Autosomal Dominant Vitreoretinochoroidopathy (ADVIRC) and Retinitis Pigmentosa (RP); and (iii) diseases with retinal and anterior segment involvement -autosomal recessive Bestrophinopathy (ARB) and Microcornea, Rod-cone dystrophy, Cataract and posterior Staphyloma (MRCS). [1][2][3][4][5][6][7] In addition to the phenotypic heterogeneity some of the bestrophinopathies display significant variation in penetrance of the clinical phenotype. 8 However, one endophenotype, the absent or reduced electrooculogram (EOG) light rise, is reported to be almost fully penetrant.…”

The molecular basis of human retinal and vitreoretinal diseases

“…Interestingly, mutations in several genes can be either dominant or recessive (Bernal et al, 2008; Bessant et al, 1999; Coppieters et al, 2007;Davidson et al, 2009; Dryja et al, 1990; Morimura et al, 1999; Pierce et al, 1999;Sullivan et al, 1999). The splicing category will now be discussed in more detail.…”

“…The disease onset and progression may vary significantly among patients, even within the same family. The patients frequently experience night blindness in the early phase of the disease, The molecular basis of human retinal and vitreoretinal diseases Collin et al, 2008; den Hollander et al, 1999; Dryja et al, 1995; Gal et al., 2000; Huang et al, 1995; Martinez-Mir et al, 1998;Maw et al, 1997;Maw et al, 2000;McLaughlin et al, 1993; Morimura et al, 1998;Nakazawa et al, 1998; Rivolta et al, 2000;Thompson et al, 2001;Tuson et al, 2004;Zangerl et al, 2006;Zhang et al, 2007b) or dominant (Abid et al, 2006; Bowne et al, 2002; Chakarova et al, 2002; Chakarova et al, 2007;Farrar et al, 1991;Freund et al, 1997;Friedman et al, 2009; Kajiwara et al, 1991; Kajiwara et al, 1994; Keen et al, 2002; Kennan et al, 2002;McKie et al, 2001; Rebello et al, 2004; Sato et al, 2005;Vithana et al, 2001;Wada et al, 2001;Zhang et al, 2007a;Zhao et al, 2009), as well as X-linked (Meindl et al, 1996; Roepman et al, 1996a; Roepman et al, 1996b; Schwahn et al, 1998).Interestingly, mutations in several genes can be either dominant or recessive (Bernal et al, 2008; Bessant et al, 1999; Coppieters et al, 2007;Davidson et al, 2009; Dryja et al, 1990; Morimura et al, 1999; Pierce et al, 1999;Sullivan et al, 1999). The splicing category will now be discussed in more detail.…”