Alternative titles; symbols
HGNC Approved Gene Symbol: BEST1
SNOMEDCT: 711162004, 723828008, 763387005;
Cytogenetic location: 11q12.3 Genomic coordinates (GRCh38) : 11:61,949,821-61,965,515 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q12.3 | ?Microcornea, rod-cone dystrophy, cataract, and posterior staphyloma 2 | 193220 | Autosomal dominant | 3 |
| Bestrophinopathy, autosomal recessive | 611809 | 3 | ||
| Macular dystrophy, vitelliform, 2 | 153700 | Autosomal dominant | 3 | |
| Retinitis pigmentosa-50 | 613194 | 3 | ||
| Retinitis pigmentosa, concentric | 613194 | 3 | ||
| Vitreoretinochoroidopathy | 193220 | Autosomal dominant | 3 |
BEST1 belongs to the bestrophin family of anion channels, which includes BEST2 (607335), BEST3 (607337), and BEST4 (607336). Bestrophins are transmembrane (TM) proteins that share a homology region containing a high content of aromatic residues, including an invariant arg-phe-pro (RFP) motif. The bestrophin genes share a conserved gene structure, with almost identical sizes of the 8 RFP-TM domain-encoding exons and highly conserved exon-intron boundaries. Each of the 4 bestrophin genes has a unique 3-prime end of variable length (Stohr et al., 2002; Tsunenari et al., 2003).
To identify the gene that is mutant in an early-onset form of vitelliform macular dystrophy (VMD2; 153700), also known as Best macular dystrophy, Petrukhin et al. (1998) defined the minimum genetic region on chromosome 11 by recombination breakpoint analysis, and scanned PAC clones of the region. They identified a novel retina-specific gene, designated VMD2, that encodes a 585-amino acid protein with a molecular mass of 68 kD and an isoelectric point of 6.9. The hydropathy profile predicted the presence of at least 4 putative transmembrane domains. Alternatively, these stretches of hydrophobic amino acids may be involved in the formation of hydrophobic pockets or may interact tightly with the membrane without crossing it. The 3-prime untranslated region (UTR) of the gene contains a region of antisense complementarity to the 3-prime UTR of the ferritin heavy-chain gene (FTH1; 134770), suggesting the possibility of antisense interaction between VMD2 and FTH1 transcripts. A mouse VMD2 probe representing a protein fragment with 89% identity to human VMD2 demonstrated exquisitely specific expression in the retinal pigment epithelium (RPE) of the adult mouse eye; similar results were seen in the human retina. The only other site of VMD2 gene expression identified by in situ hybridization was Sertoli cells in mouse testis. Petrukhin et al. (1998) proposed the name 'bestrophin' for the protein encoded by the VMD2 gene.
Marquardt et al. (1998) pursued further the work of Stohr et al. (1998) in identifying novel genes located within the critical region for Best disease on 11q13. They characterized 9 novel genes, determining their expression profiles as well as their genomic organizations, and analyzed their exonic sequences for the presence of mutations in patients from multigenerational Best disease pedigrees. By Northern blot analysis, one of the genes, termed TU15B, was found to be expressed exclusively in retinal pigment epithelium (RPE) as a single 2.4-kb transcript. Database analysis of the putative translation product of TU15B revealed a high degree of sequence conservation throughout evolution.
Using rabbit polyclonal and mouse monoclonal antibodies and immunocytochemical staining of macaque and porcine eyes, Marmorstein et al. (2000) found that bestrophin is localized at the basolateral plasma membrane of RPE cells. This localization suggested that bestrophin may play a role in generating the altered electrooculogram of individuals with Best disease.
Goodstadt and Ponting (2001) used the prediction of enzymatic activity for bestrophin as an example of how genetic databases can expand understanding of genes of unknown function by identifying homologies and functional motifs.
Using heterologous expression, Sun et al. (2002) showed that the human, Drosophila, and C. elegans bestrophin homologs form oligomeric chloride channels, and that human bestrophin is sensitive to intracellular calcium. Each of 15 missense mutations associated with vitelliform macular dystrophy greatly reduced or abolished the membrane current. Four of these mutant bestrophins were coexpressed with wildtype and each dominantly inhibited the wildtype membrane current, consistent with the dominant nature of the disorder. These experiments established the existence of a new chloride channel family and VMD as a channelopathy.
By whole-cell recordings of BEST1-transfected 293 cells, Sun et al. (2002) and Tsunenari et al. (2003) detected a weakly outward-rectifying current in response to a negative voltage step. Tsunenari et al. (2003) did not find new chloride currents in Xenopus oocytes following injection of BEST1 cRNA, suggesting that human cells contain a factor or subunit required for bestrophin function or plasma membrane localization.
Using Western blot analysis and confocal microscopy, Duta et al. (2004) showed that bestrophin was expressed in a human lung adenocarcinoma cell line. Bestrophin-directed small interfering RNA reduced the movement of radioactive chloride across cell monolayers. Duta et al. (2004) concluded that bestrophin contributes to the basolateral cell conductance in airway epithelial cells.
Although phasic GABA release arises from Ca(2+)-dependent exocytosis from neurons, the mechanism of tonic GABA release was unknown. Lee et al. (2010) reported that tonic inhibition in the cerebellum is due to GABA being released from glial cells by permeation of the bestrophin-1 (Best1) anion channel. They demonstrated that GABA directly permeates Best1 to yield GABA release and that tonic inhibition is eliminated by silencing of Best1. Glial cells express both GABA and Best1, and selective expression of Best1 in glial cells, after preventing general expression of Best1, fully rescues tonic inhibition. Lee et al. (2010) concluded that their results identified a molecular mechanism for tonic inhibition and established a role for interactions between glia and neurons in mediating tonic inhibition.
Moshfegh et al. (2016) found that mutations in BEST1 associated with VMD2 affected highly conserved residues. Structural modeling predicted that these BEST1 mutations would disrupt stability of pentamer formation and affect channel function. Studies of wildtype and patient stem cell-derived RPE cells suggested that BEST1 mediates chloride ion efflux in RPE cells.
Crystal Structure
Yang et al. (2014) described the structure of a bacterial homolog (KpBest) of BEST1 as well as functional characterizations of both channels. KpBest is a pentamer that forms a 5-helix transmembrane pore, closed by 3 rings of conserved hydrophobic residues, and has a cytoplasmic cavern with a restricted exit. From electrophysiologic analysis of structure-inspired mutations in KpBest and BEST1, Yang et al. (2014) found a sensitive control of ion selectivity in the bestrophins, including reversal of anion/cation selectivity, and dramatic activation by mutations at the cytoplasmic exit. Yang et al. (2014) also created a homology model of BEST1 that shows the locations of disease-causing mutations and suggests possible roles in regulation.
Dickson et al. (2014) presented the x-ray crystal structures of chicken BEST1-Fab complexes at 2.85-angstrom resolution with permeant anions and Ca(2+). Representing the first structure of a calcium-activated chloride channel, the eukaryotic BEST1 channel is formed from a pentameric assembly of subunits. Ca(2+) binds to the channels large cytosolic region. A single ion pore approximately 95 angstroms in length is located along the central axis and contains at least 15 binding sites for anions.
Vitelliform Macular Dystrophy 2
In several Swedish and Dutch families with Best macular dystrophy (VMD2; 153700), including a large Swedish family reported by Nordstrom and Barkman (1977) and studied by Graff et al. (1997), Petrukhin et al. (1998) identified 5 different heterozygous mutations in the VMD2 gene (607854.0001-607854.0005) that segregated with the disease.
In 12 patients with Best macular dystrophy, Marquardt et al. (1998) identified heterozygous sequence changes in the TU15B gene (see, e.g., 607854.0006). For 10 sequence changes, segregation with the disease was shown in multigenerational families. These data provided strong evidence that TU15B is the VMD2 gene.
Bakall et al. (1999) analyzed the bestrophin gene in 14 unrelated Swedish, Dutch, Danish, and Moroccan families with Best macular dystrophy and identified 8 previously unreported mutations. No mutations were detected in 3 families. The authors noted that the 19 mutations identified to date were missense mutations aggregating in 4 regions of the gene, and suggested that null alleles might result in other ocular diseases.
In 2 unrelated women who had vitelliform macular dystrophy diagnosed in the sixth decade of life, Allikmets et al. (1999) identified heterozygous missense mutations in the BEST1 gene (E119Q, 607854.0008; A146K, 607854.0009).
Caldwell et al. (1999) analyzed the bestrophin gene in 13 families with Best macular dystrophy and identified mutations in 9 families, including 6 missense mutations and a 2-bp deletion (607854.0012). The deletion occurred in exon 10; the authors stated that this was the first mutation reported in the 3-prime half of the bestrophin gene, beyond exon 8. In 3 of the families, there was a parent carrying the mutation who lacked the clinical phenotype, suggesting variable expression of the disease gene.
Kramer et al. (2000) identified several mutations in the VMD2 gene in German patients with macular dystrophy of juvenile onset as well as in 8 of 32 patients with adult-onset disease who were negative for mutation in the PRPH2 gene (see, e.g., 607854.0005 and 607854.0010-607854.0011). The authors suggested that the adult-onset patients represented a mild form of Best disease.
White et al. (2000) stated that 48 different mutations, predominantly missense mutations, had been described in the VMD2 gene in Best disease families. For the most part, these mutations affected amino acids in the first 50% of the protein and occurred in 4 distinct clusters possibly representing regions of functional importance. Results of analysis in 2 large series of patients with age-related macular degeneration (see 603785) suggested that the VMD2 gene does not play a major role in this disorder (Kramer et al., 2000; Allikmets et al., 1999).
Schatz et al. (2006) reported 6 affected members of a Swedish family with Best macular dystrophy who had mutations in the BEST1 gene. Four were heterozygous for either an R141H (607854.0013) or a Y29X (607854.0014) mutation and 2 were compound heterozygous for these mutations. The latter 2 patients presented with a variant form of the disorder. Both had onset of visual symptoms in early childhood and markedly reduced visual acuities. Fundus examination and OCT scan showed degenerative yellowish changes in the macula, thickening and elevation of the outer retina-RPE-choroid complex, and cystic edema of the macula.
Katagiri et al. (2015) performed a mutation analysis of the BEST1 and PRPH2 genes in 16 Japanese families with typical features of VMD and identified 12 different BEST1 variants in 13 probands (81%). Two of the variants were novel and 10 had previously been reported. Twelve probands had heterozygous mutations and 1 proband had compound heterozygous mutations. No mutations were identified in the PRPH2 gene.
Bestrophinopathy, Autosomal Recessive
Burgess et al. (2008) described a retinal disorder, which they designated autosomal recessive bestrophinopathy (ARB; 611809), caused by biallelic mutation in BEST1 (e.g., 607854.0013 and 607854.0017) and associated with central visual loss, a characteristic retinopathy, an absent electrooculogram light rise, and a reduced electroretinogram. In 5 families, DNA variants were identified in each of 10 alleles. These encoded 6 different missense variants and 1 nonsense variant. No clinical or electrophysiologic abnormalities were found in heterozygotes. Two ARB missense isoforms severely reduced chloride channel activity. However, unlike 2 other alleles previously associated with Best disease, cotransfection with wildtype bestrophin-1 did not impair the formation of active wildtype bestrophin-1 channels, consistent with the recessive nature of the condition. Burgess et al. (2008) proposed that ARB is a null phenotype of bestrophin-1 in humans.
Vitreoretinochoroidopathy
Yardley et al. (2004) sequenced the BEST1 gene in 5 families with autosomal dominant developmental eye abnormalities associated with retinal dystrophy (see vitreoretinochoroidopathy, or ADVIRC, 193220), and identified 3 different heterozygous missense mutations (V86M, 607854.0019; V239M, 607854.0020; and Y236C, 607854.0021). In vitro functional assays demonstrated that all 3 of these mutations disrupted splicing and caused exon skipping, whereas 2 mutations in close proximity that are known to cause Best disease, Y85H (607854.0002) and A243T, did not. Screening of the BEST1 gene in 18 unrelated individuals with microphthalmia/coloboma (see MCOPCB1, 300345) and 50 individuals with various forms of anterior segment dysgenesis revealed no pathogenic alterations.
Retinitis Pigmentosa 50
In the proband of a nonconsanguineous family of European descent segregating autosomal dominant retinitis pigmentosa (adRP) mapping to chromosome 11 (RP50; 613194), Davidson et al. (2009) sequenced the BEST1 gene and identified heterozygosity for a missense mutation (I205T; 607854.0022) that segregated with disease in the family. Analysis of BEST1 in a panel of 95 adRP patients who were negative for mutation in 10 known RP genes and in 12 patients with concentric RP revealed heterozygosity for a D228N missense mutation (607854.0023) in affected members of 1 adRP family and 1 concentric RP family, and heterozygosity for a Y227C mutation (607854.0024) in another concentric RP family. Homozygosity for a missense mutation in BEST1 (L140V; 607854.0025) was found in affected members of a Pakistani family that appeared to be segregating adRP, but in which the parents were from the same village.
In an affected sister and brother from a family segregating autosomal dominant vitreoretinochoroidopathy (ADVIRC), Burgess et al. (2009) identified heterozygosity for a 704T-C transition in the BEST1 gene (V235A; 607854.0026). Analysis of exonic splice enhancer (ESE) activity in exon 6 of the BEST1 gene demonstrated that 2 ADVIRC-associated mutations, V235A and Y236C (607854.0021; 707A-G), weakened or abolished ESE site-dependent splicing, respectively, whereas a Best disease-associated mutation (V235L; 703G-C; see Yardley et al., 2004) strengthened ESE activity compared to wildtype. In addition, gel-shift assays involving serine/arginine (SR)-rich proteins, such as SFRS1 (600812), showed that SFRS1 had increased binding to the V235A- or V236C-mutant sequences compared to wildtype or V235L-mutant sequence. Given the exon skipping observed with the ADVIRC-associated mutations and their affinity for SFRS1, Burgess et al. (2009) suggested that the region encompassing V235A and Y236C mutations (nucleotides 704 to 709) may form part of a composite exonic regulatory elements of splicing (CERES) site.
Milenkovic et al. (2018) found that pathologic mutations affecting highly conserved residues in the N-terminal half of BEST1 likely affect protein stability. Analysis of BEST1 half-life in transfected canine MDCKII cells confirmed that BEST1 mutations enhanced protein instability. BEST1 proteins with autosomal recessive mutations were degraded more quickly than wildtype BEST1 or BEST1 proteins with autosomal dominant mutations due to the use of different degradation mechanisms. BEST1 proteins with autosomal recessive mutations were recognized by the endoplasmic reticulum (ER) and subsequently degraded, whereas BEST1 proteins with autosomal dominant mutations escaped the ER quality check and were degraded by a post-ER quality control mechanism at the Golgi complex.
Esumi et al. (2009) showed that the -154 to -104 bp region of the Best1 gene is necessary for retinal pigment epithelium (RPE) expression in transgenic mice. The Best1 promoter region contains a predicted canonical OTX-binding site (-127 to -122 bp) and a neighboring noncanonical OTX-binding site (-81 to -76 bp), and mutation of either OTX-binding site results in reduced promoter activity. The 3 OTX family proteins, OTX1 (600036), OTX2 (600037), and CRX (602225) bound to both OTX-binding sites in vitro, and all of them increased BEST1 promoter activity. Human and bovine RPE expressed not only OTX2 but also CRX, and both OTX2 and CRX bound to the BEST1 proximal promoter region in vivo.
Zhang et al. (2010) generated knockin mice carrying the Best vitelliform macular dystrophy-causing mutation W93C (607854.0001) in Best1. Both Best1(+/W93C) and Best1(W93C/W93C) mice had normal ERG a- and b-waves, but exhibited an altered light peak luminance response reminiscent of that observed in BVMD patients. Morphologic analysis identified fluid- and debris-filled retinal detachments in mice as young as 6 months of age. By 18 to 24 months of age, Best1(+/W93C) and Best1(W93C/W93C) mice exhibited enhanced accumulation of lipofuscin in the RPE, and a significant deposition of debris composed of unphagocytosed photoreceptor outer segments and lipofuscin granules in the subretinal space. The RPE cells from Best1(W93C) mice exhibited normal chloride conductances, and ATP-stimulated changes in calcium concentration in RPE cells from Best1(+/W93C) and Best1(W93C/W93C) mice were suppressed relative to Best1 +/+ littermates. The authors hypothesized that BVMD does not occur because of Best1 deficiency, as the phenotypes of Best1(+/W93C0) and Best1(W93C/W93C) mice are distinct from that of Best1 -/- mice with regard to lipofuscin accumulation and changes in the light peak and ATP calcium responses.
In affected members of a large Swedish family with Best macular dystrophy (VMD2; 153700) first reported by Nordstrom and Barkman (1977), Petrukhin et al. (1998) identified heterozygosity for a 383G-C transversion in exon 4 of the VMD2 gene, resulting in a trp93-to-cys (W93C) amino acid substitution. The W93C mutation in this Swedish family was not found in 50 unrelated individuals of predominantly European descent or in 50 healthy Swedish blood donors. One of the affected family members was homozygous for W93C; Nordstrom and Barkman (1977) had noted that there was no difference in phenotype between heterozygotes and apparent homozygotes.
In affected members of a Swedish family with Best macular dystrophy (VMD2; 153700), Petrukhin et al. (1998) identified heterozygosity for a 357T-C transition in the VMD2 gene, resulting in a tyr85-to-his (Y85H) substitution. All related proteins from C. elegans contained tyrosine or isofunctional phenylalanine in this position; tyrosine is highly similar to phenylalanine in that it also is an aromatic hydrophobic amino acid. The Y85H mutation was found to cosegregate with the disease in all affected members of the pedigree and was not detected in 200 chromosomes from normal individuals of North American and Swedish descent.
In affected members of a Swedish family with Best macular dystrophy (VMD2; 153700), Petrukhin et al. (1998) identified heterozygosity for a 1000G-A transition in the VMD2 gene, resulting in a gly299-to-glu (G299E) substitution. The G299E mutation was found in all affected members of this Swedish pedigree and was not found in 94 normal chromosomes from the Swedish sample.
In all affected members of an Iowa family of Dutch ancestry with Best macular dystrophy (VMD2; 153700), originally reported by Braley and Spivey (1964), Petrukhin et al. (1998) identified a heterozygous 783T-A transversion in the VMD2 gene, resulting in a tyr227-to-asn (Y227N) substitution. All related proteins from C. elegans contained tyrosine or isofunctional phenylalanine in this position.
Mullins et al. (2005) restudied a male mutation carrier from this pedigree who had photographically documented normal maculae at age 51 years, but subsequently developed small vitelliform lesions at age 75 years, followed by widespread flecks in the midperiphery; 2 additional family members exhibited similar multifocal lesions.
In affected members from 2 unrelated Dutch families with Best macular dystrophy (VMD2; 153700), Petrukhin et al. (1998) identified heterozygosity for a 120A-C transversion in the VMD2 gene, resulting in a thr6-to-pro (T6P) substitution. Analysis of this residue among 14 C. elegans proteins had not shown this threonine to be conserved. However, the authors classified the 120A-C change as a disease mutation because thr6 is located next to the evolutionarily conserved tyrosine at amino acid position 5, and a Chou-Fasman algorithm predicted a dramatic change in the secondary structure as a result of the threonine to proline substitution.
In a German patient with adult-onset vitelliform macular dystrophy, Kramer et al. (2000) identified heterozygosity for the T6P mutation in exon 2 of the VMD2 gene. There was no family history of the disorder.
In 2 patients with Best dystrophy who exhibited multifocal lesions, Boon et al. (2007) identified heterozygosity for the T6P mutation in the VMD2 gene.
In affected members of 2 unrelated families with Best macular dystrophy (VMD2; 153700), 1 from Germany and 1 from Canada, Marquardt et al. (1998) found a heterozygous deletion of codon 295, an isoleucine, in the VMD2 gene.
Among 10 missense mutations identified in the VMD2 gene in association with Best macular dystrophy (VMD2; 153700), Marquardt et al. (1998) identified a val9-to-met (V9M) amino acid substitution in exon 2 of the VMD2 gene resulting from a GTG-to-ATG transition.
In a 61-year-old woman with vitelliform macular dystrophy (VMD2; 153700) diagnosed at age 57 years, who had mottling of the retinal pigment epithelium in the right eye and exhibited a bull's-eye configuration in her left eye, Allikmets et al. (1999) identified heterozygosity for a 355G-C transversion in the VMD2 gene, resulting in a glu119-to-gln (E119Q) substitution.
In a 60-year-old woman with vitelliform macular dystrophy (VMD2; 153700) diagnosed at age 54 years, Allikmets et al. (1999) identified a heterozygous 540GC-AA change in the VMD2 gene, resulting in an ala146-to-lys (A146K) substitution.
In 8 unrelated patients with vitelliform macular dystrophy (VMD2; 153700), 3 with onset of disease in childhood and 5 with onset in adulthood, Kramer et al. (2000) identified heterozygosity for a 728C-T transition in exon 7 of the BEST1 gene, resulting in an ala243-to-val (A243V) substitution. Four of the patients, 3 with childhood-onset disease and 1 with adult-onset, had a first-degree affected relative who also carried the mutation.
In a sporadic patient with adult-onset vitelliform macular dystrophy (VMD2; 153700), Kramer et al. (2000) identified a heterozygous 140G-A transition in exon 2 of the VMD2 gene, resulting in an arg47-to-his (R47H) substitution.
In a patient with Best macular dystrophy (VMD2; 153700), Caldwell et al. (1999) identified heterozygosity for a 2-bp deletion (1574delCA) in exon 10 of the VMD2 gene, causing a frameshift resulting in a premature termination codon 24 amino acids downstream that truncates the protein by 71 amino acids. The authors stated that this was the first mutation reported in the 3-prime half of the bestrophin gene, beyond exon 8.
In 6 affected members of Swedish family with Best macular dystrophy (VMD2; 153700), Schatz et al. (2006) identified mutations in the BEST1 gene. One was heterozygous for an arg141-to-his (R141H) mutation, 3 were heterozygous for a tyr29-to-ter (Y29X; 607854.0014) mutation, and 2 were compound heterozygous for these mutations. The 2 members who were compound heterozygous had a more severe phenotype. Neither mutation was found in 100 Swedish control individuals.
In a 15-year-old proband with multifocal Best vitelliform macular dystrophy, Wittstrom et al. (2011) identified compound heterozygosity for 2 mutations in the BEST1 gene: the R141H mutation and a de novo pro233-to-ala (P233A) substitution. The R141H mutation was present in heterozygous state in her mother and brother, neither of whom had any visual symptoms. However, both heterozygous carriers showed delayed implicit times in a- and b-waves of combined total rod and cone full-field ERG responses.
In 2 patients with a distinctive retinopathy, called bestrophinopathy (ARB; 611809), Burgess et al. (2008) identified compound heterozygosity for missense mutations in the BEST1 gene. Both patients carried a 442G-A transition that caused the R141H substitution; 1 patient also had a 949G-A transition resulting in a val317-to-met substitution (V317M; 607854.0017), and the other patient had a 122T-C transition causing a leu41-to-pro substitution (L41P; 607854.0018).
For discussion of the tyr29-to-ter (Y29X) mutation in the BEST1 gene that was found in compound heterozygous state in patients with Best macular dystrophy (VMD2; 153700) by Schatz et al. (2006), see 607854.0013.
In a brother and sister with a distinctive retinopathy, designated bestrophinopathy (ARB; 611809), Burgess et al. (2008) identified homozygosity for a 598C-T transition in the BEST1 gene that caused truncation of the protein (arg200 to ter; R200X). The age at visual deterioration was 30 years in the brother and 18 years in the sister.
In a patient reported by Burgess et al. (2008) with autosomal recessive bestrophinopathy (ARB; 611809), a val317-to-met (V317M) mutation occurred in compound heterozygosity with R141H (607854.0013). Visual deterioration began at age 40 years.
In a patient reported by Burgess et al. (2008) with autosomal recessive bestrophinopathy (ARB; 611809), a leu41-to-pro (L41P) mutation in the BEST1 gene occurred in compound heterozygosity with R141H (607854.0013). Visual deterioration began at age 4 years.
In affected members of 3 families segregating autosomal dominant vitreoretinochoroidopathy, microcornea, glaucoma, and cataract (VRCP; 193220), including the 4-generation Belgian family previously reported by Lafaut et al. (2001), a 6-generation French family originally reported by Hermann (1958), and another Belgian family, Yardley et al. (2004) identified heterozygosity for a 256G-A transition in exon 4 of the BEST1 gene, resulting in a val86-to-met (V86M) substitution at a conserved residue. In vitro functional assays demonstrated that V86M disrupts splicing and causes exon skipping. The mutation was not found in 400 control chromosomes.
In affected members of a 3-generation English family with microcornea, rod-cone dystrophy, cataract, and posterior staphyloma (MRCS2; 193220), originally reported by Reddy et al. (2003), Yardley et al. (2004) identified heterozygosity for a 715G-A transition in exon 7 of the BEST1 gene, resulting in a val239-to-met (V239M) substitution at a conserved residue. In vitro functional assays demonstrated that V239M disrupts splicing and causes exon skipping. The mutation was not found in 400 control chromosomes.
In affected members of a family segregating autosomal dominant vitreoretinochoroidopathy and nanophthalmos (VRCP; 193220), Yardley et al. (2004) identified heterozygosity for a 707A-G transition in exon 6 of the BEST1 gene, resulting in a tyr236-to-cys (Y236C) substitution at a conserved residue. In vitro functional assays demonstrated that Y236C disrupts splicing and causes exon skipping. The mutation was not found in 400 control chromosomes.
Burgess et al. (2009) analyzed exonic splice enhancer (ESE) activity in exon 6 of the BEST1 gene and found that the 707A-G variant abolished ESE site-dependent splicing. Gel-shift assays involving serine/arginine (SR)-rich proteins showed that SFRS1 (600812) had increased binding to 707A-G compared to wildtype.
In 10 affected members of a family with retinitis pigmentosa-50 (RP50; 613194), Davidson et al. (2009) identified heterozygosity for a 614T-C transition in exon 5 of the BEST1 gene, resulting in an ile205-to-thr (I205T) substitution. The mutation was not found in 5 unaffected family members or in 210 ethnically matched control chromosomes.
In a mother and son with retinitis pigmentosa-50 (RP50; 613194) and a brother and sister with concentric RP (see 613194), Davidson et al. (2009) identified heterozygosity for a 682G-A transition in exon 6 of the BEST1 gene, resulting in an asp228-to-asn (D228N) substitution. The mutation was not found in 210 ethnically matched control chromosomes.
In affected members of a German family with vitelliform macular dystrophy (VMD2; 153700), Marquardt et al. (1998) identified heterozygosity for a 680A-G transition in exon 6 of the BEST1 gene, resulting in a tyr227-to-cys (Y227C) substitution at a highly conserved residue. The mutation, which segregated with disease, was not found in 84 control chromosomes.
In a 45-year-old woman with concentric retinitis pigmentosa (see 613194), Davidson et al. (2009) identified heterozygosity for the BEST1 Y227C mutation. Funduscopic examination revealed an abrupt change from normal to abnormal retina in the periphery, suggestive of a bestrophinopathy (611809), but after detection of the Y227C mutation, adjacent to the D228N (607854.0023) mutation that had been found in a family with concentric RP, the fundus images were considered to be consistent with concentric RP. The patient had 2 affected daughters with a similar phenotype who were unavailable for molecular testing.
In a father and 2 daughters from a Pakistani family with retinitis pigmentosa-50 (RP50; 613194), Davidson et al. (2009) identified homozygosity for a 418C-G transversion in exon 4 of the BEST1 gene, resulting in a leu140-to-val (L140V) substitution. Davidson et al. (2009) stated that in unpublished results, they had previously found the L140V mutation in patients diagnosed with autosomal recessive bestrophinopathy (ARB; 611809).
In an affected sister and brother from a family segregating autosomal dominant vitreoretinochoroidopathy (VRCP; 193220), Burgess et al. (2009) identified heterozygosity for a 704T-C transition in exon 6 of the BEST1 gene, predicted to result in a val235-to-ala (V235A) substitution. The mutation was not found in 210 control chromosomes. Splicing assay in HEK293 cells demonstrated the generation of both wildtype product and a larger splice product including an extra copy of exon 6, spliced between exons 6 and 7. Analysis of exonic splice enhancer (ESE) activity in exon 6 of the BEST1 gene demonstrated that the 704T-C variant weakened ESE site-dependent splicing compared to wildtype, and gel-shift assays involving serine/arginine (SR)-rich proteins showed that SFRS1 (600812) had increased binding to 704T-C compared to wildtype.
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