{{Short description|Protein-coding gene in the species Homo sapiens}} thumb|Calcium-activated chloride channel bestrophin-1 (BEST1), triple mutant: I76A, F80A, F84A; in complex with an Fab antibody fragment, chloride, and calcium. Secondary structure of biological assembly 1 viewed via front C5 axis orientation. From RCSB PDB.{{Infobox_gene}} '''Bestrophin-1''' (Best1) is a protein that, in humans, is encoded by the ''BEST1'' gene (RPD ID - 5T5N/4RDQ).<ref name="entrez">{{cite web | title = Entrez Gene: BEST1 bestrophin 1| url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=7439}}</ref>
The bestrophin family of proteins comprises four evolutionary related genes (BEST1, BEST2, BEST3, and BEST4) that code for integral membrane proteins.<ref name="Kunzelmann_2015">{{cite journal | vauthors = Kunzelmann K | title = TMEM16, LRRC8A, bestrophin: chloride channels controlled by Ca(2+) and cell volume | journal = Trends in Biochemical Sciences | volume = 40 | issue = 9 | pages = 535–43 | date = September 2015 | pmid = 26254230 | doi = 10.1016/j.tibs.2015.07.005 | department = review }}</ref> This family was first identified in humans by linking a BEST1 mutation with Best vitelliform macular dystrophy (BVMD).<ref name="Johnson_2017">{{cite journal | vauthors = Johnson AA, Guziewicz KE, Lee CJ, Kalathur RC, Pulido JS, Marmorstein LY, Marmorstein AD | title = Bestrophin 1 and retinal disease | journal = Progress in Retinal and Eye Research | volume = 58 | pages = 45–69 | date = January 2017 | pmid = 28153808 | pmc = 5600499 | doi = 10.1016/j.preteyeres.2017.01.006 | department = review }}</ref> Mutations in the BEST1 gene have been identified as the primary cause for at least five different degenerative retinal diseases.<ref name="Johnson_2017" />
The bestrophins are an ancient family of structurally conserved proteins that have been identified in nearly every organism studied from bacteria to humans. In humans, they function as calcium-activated anion channels, each of which has a unique tissue distribution throughout the body. Specifically, the BEST1 gene on chromosome 11q13 encodes the Bestrophin-1 protein in humans whose expression is highest in the retina.<ref name="Johnson_2017"/>
== Structure ==
=== Gene ===
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 four bestrophin genes has a unique 3-prime end of variable length.<ref name="entrez" />
BEST1 has been shown by two independent studies to be regulated by Microphthalmia-associated transcription factor.<ref name="pmid17085443">{{cite journal | vauthors = Esumi N, Kachi S, Campochiaro PA, Zack DJ | title = VMD2 promoter requires two proximal E-box sites for its activity in vivo and is regulated by the MITF-TFE family | journal = The Journal of Biological Chemistry | volume = 282 | issue = 3 | pages = 1838–50 | date = January 2007 | pmid = 17085443 | doi = 10.1074/jbc.M609517200 | department = primary | doi-access = free }}</ref><ref name="pmidunknown">{{cite journal | vauthors = Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, Valgeirsdottir S, Bergsteinsdottir K, Schepsky A, Dummer R, Steingrimsson E | title = Novel MITF targets identified using a two-step DNA microarray strategy | journal = Pigment Cell & Melanoma Research | volume = 21 | issue = 6 | pages = 665–76 | date = December 2008 | pmid = 19067971 | doi = 10.1111/j.1755-148X.2008.00505.x | s2cid = 24698373 | department = primary | doi-access = free }}</ref>
=== Protein ===
Bestrophin-1 is an integral membrane protein found primarily in the retinal pigment epithelium (RPE) of the eye.<ref name="Strauss_2012">{{cite book | vauthors = Strauss O, Neussert R, Müller C, Milenkovic VM | title = Retinal Degenerative Diseases | chapter = A potential cytosolic function of bestrophin-1 | volume = 723 | pages = 603–10 | year = 2012 | pmid = 22183384 | doi = 10.1007/978-1-4614-0631-0_77 | series = Advances in Experimental Medicine and Biology | isbn = 978-1-4614-0630-3 | department = review }}</ref> Within the RPE layer, it is mainly located on the basolateral plasma membrane. Protein crystallization structures indicate this protein's primary ion channel function as well as its calcium regulatory capabilities.<ref name="Strauss_2012" /><ref name="Johnson_2017"/> Bestrophin-1 consists of 585 amino acids and both N- and the C-termini are located within the cell. thumb|Calcium-activated chloride channel bestrophin-1 (BEST1), triple mutant: I76A, F80A, F84A; in complex with an Fab antibody fragment, chloride, and calcium. Subunit structure of Biological Assembly 1 viewed via side edge-centered orientation. From RCSB PDB The structure of Best1 consists of five identical subunits that each span the membrane four times and form a continuous, funnel-shaped pore via the second transmembrane domain containing a high content of aromatic residues, including an invariant arg-phe-pro (RFP) motif.<ref name="Johnson_2017" /><ref name="pmid18391176">{{cite journal | vauthors = Hartzell HC, Qu Z, Yu K, Xiao Q, Chien LT | title = Molecular physiology of bestrophins: multifunctional membrane proteins linked to best disease and other retinopathies | journal = Physiological Reviews | volume = 88 | issue = 2 | pages = 639–72 | date = April 2008 | pmid = 18391176 | doi = 10.1152/physrev.00022.2007 | department = review }}</ref><ref name="Xiao_20102">{{cite journal | vauthors = Xiao Q, Hartzell HC, Yu K | title = Bestrophins and retinopathies | journal = Pflügers Archiv | volume = 460 | issue = 2 | pages = 559–69 | date = July 2010 | pmid = 20349192 | pmc = 2893225 | doi = 10.1007/s00424-010-0821-5 | department = review }}</ref> The pore is lined with various nonpolar, hydrophobic amino acids. Both the structure and the composition of the pore help to ensure that only small anions are able to move completely through the channel. The channel acts as two funnels working together in tandem. It begins with a semi-selective, narrow entryway for anions, and then opens to a larger, positively charged area which then leads to a narrower pathway that further limits the size of anions passing through the pore. A calcium clasp acts as a belting mechanism around the larger, middle section of the channel. Calcium ions control the opening and closing of the channel due to conformational changes caused by calcium binding at the C-terminus directly following the last transmembrane domain.<ref name="Johnson_2017" /><ref name="Xiao_20102"/>
== Tissue and subcellular distribution ==
The location of expression of the BEST1 gene is essential for protein functioning and mislocalization is often connected to a variety of retinal degenerative diseases. The BEST1 gene expresses the Best1 protein primarily in the cytosol of the retinal pigment epithelium. The protein is typically contained in vesicles near the cellular membrane. There is also research to support that the Best1 protein is localized and produced in the endoplasmic reticulum (intracellular organelle involved in protein and lipid synthesis). Best1 is typically expressed with other proteins also synthesized in the endoplasmic reticulum, such as calreticulin, calnexin and Stim-1. Calcium ion involvement in the countertransport of chloride ions also supports the idea that Best1 is involved in forming calcium stores within the cell.<ref name="Strauss_2012"/>
== Function ==
Best1 primarily functions as an intracellular calcium-activated chloride channel on the cellular membrane that is not voltage-dependent.<ref name="Kunzelmann_2015"/><ref name="Strauss_2012"/><ref name="Xiao_20102"/> More recently Best1 has been shown to act as a volume-regulating anion channel.
==Diseases ==
=== Best vitelliform macular dystrophy (BVMD) === thumb|Lipofuscin (lipid residual from lysosome digestion) in a human neuron. Representative of what may occur in the eye in people affected by BMVD. Best's vitelliform macular dystrophy (BVMD) is one of the most common Best1-associated diseases. BVMD typically becomes noticeable in children and is represented by the buildup of lipofuscin (lipid residuals) lesions in the eye.<ref name="Kunzelmann_2015"/><ref name="Strauss_2012"/> Diagnosis normally follows an abnormal electrooculogram in which decreased activation of calcium channels in the basolateral membrane of the retinal pigment epithelium becomes apparent. A mutation in the BEST1 gene leads to a loss of channel function and eventually retinal degeneration.<ref name="Strauss_2012" /> Although BVMD is an autosomal dominant form of macular dystrophy, expressivity varies within and between affected families although the overwhelming majority of affected families come from northern European descent.<ref name="Johnson_2017" /><ref name="Strauss_2012" /> Typically, people with this condition experience five progressively worsening stages, though timing and severity varies greatly. BVMD is often caused by the single missense mutations; however, amino acid deletions have also been identified.<ref name="Johnson_2017" /> A loss of function of the Best1 chloride channel could likely explain some of the most common issues associated with BVMD: an inability to regulate intracellular ion concentrations and regulate overall cell volume.<ref name="Strau_2014">{{cite book | chapter = The Role of Bestrophin-1 in Intracellular Ca<sup>2+</sup> Signaling | vauthors = Olaf S, Müller C, Reichhart N, Tamm ER, Gomez NM | veditors = Ash J, Grimm C, Hollyfield JG, Anderson RE, LaVail NM, Rickman CB | title = Retinal Degenerative Diseases: Mechanisms and Experimental Therapy | volume = 801 | date = 2014 | publisher = Springer | location = New York | isbn = 978-1-4614-3209-8 | doi = 10.1007/978-1-4614-3209-8_15 | pmid = 24664688 | pages = 113–119 | department = review | series = Advances in Experimental Medicine and Biology }}</ref> To date, over 100 disease-causing mutations have been related to BVMD as well as a number of other degenerative retinal diseases.<ref name="Xiao_20102"/> Although BVMD typically presents as a bilateral maculopathy, rare cases of persistent unilateral or markedly asymmetric BEST1-associated vitelliform disease have been reported, despite bilateral electrophysiological evidence of retinal pigment epithelium dysfunction.<ref>{{cite journal |last=Arora |first=R |display-authors=etal |title=Unilateral BEST1-Associated Retinopathy |journal=American Journal of Ophthalmology |year=2016 |volume=169 |pages=24–32 |doi=10.1016/j.ajo.2016.05.024 |pmc=5016077 }}</ref><ref name="Lindamulage_UBD">{{cite web |last=Lindamulage |first=Suneth Dayan |title=The First Case Report of Unilateral Best Disease from Sri Lanka |url=https://doi.org/10.6084/m9.figshare.30090424 |website=Figshare |publisher=Figshare |access-date=19 January 2026 }}</ref> In addition to genetic modifiers, a translational conceptual framework has been proposed in the context of asymmetric or unilateral expression in Best disease, termed '''Augmented Innate Silence (AIS)'''. AIS defines “'''silence'''” as the absence of clinical disease expression despite the presence of genetic susceptibility. The concept of Augmented Innate Silence was proposed by Suneth Dayan Lindamulage and was inspired by clinical observations from the first reported case of unilateral Best disease from Sri Lanka.<ref name="Lindamulage_UBD"/> AIS suggests that '''innate''' and locally acting protective mechanisms may suppress or delay disease manifestation in one eye. The framework of Augmented Innate Silence further proposes that identifying such mechanisms may inform future strategies aimed to '''augment''' this protective '''silence''' in disease-prone eyes, thereby guiding translational research into potential disease-modifying approaches.<ref>{{cite web |title=Augmented Innate Silence (AIS): A Conceptual Framework for Inherited Retinal Diseases |url=https://doi.org/10.6084/m9.figshare.31082728 |website=Figshare |author=Lindamulage, Suneth Dayan |year=2025 |publisher=Figshare |access-date=19 January 2026 }}</ref>
=== Adult-onset vitelliform macular dystrophy (AVMD) === Adult-onset vitelliform macular dystrophy (AVMD) consists of lesions similar to BVMD on the retina. However, the cause is not as definitive as BVMD. The inability to diagnosis AVMD via genetic testing makes differentiating between AVMD and pattern dystrophy difficult. It is also unknown whether there is truly a clinical difference between AVMD caused by BEST1 mutations and AVMD caused by PRPH2 mutations. AVMD usually involves less vision loss than BVMD and cases do not usually run in families.<ref name="Johnson_2017" />
=== Autosomal recessive bestrophinopathy (ARB) === Autosomal recessive bestrophinopathy (ARB) was first identified in 2008. People with ARB demonstrate a decrease in vision during the first ten years of life. Parents and family members typically show no abnormalities as the disease is autosomal recessive, indicating that both alleles of the BEST1 gene must be mutated. Vitelliform lesions are often present and some cases involve cystoid macular edema. In addition, other complications have been observed. Vision decreases slowly over time, although rates of decline vary. Mutations causing ARB range from missense mutations to single base mutations in non-coding regions.<ref name="Johnson_2017" />
thumb|Cataract in human eye, potentially caused by autosomal dominant vitreoretinochoroidopathy.
=== Autosomal dominant vitreoretinochoroidopathy === Autosomal dominant vitreoretinochoroidopathy was first identified in 1982 and presents itself in both eyes with decreases in peripheral vision due to excessive fluid and changes in eye retinal pigmentation. Early onset cataracts are also likely.<ref name="Johnson_2017" />
=== Retinitis pigmentosa (RP) === thumb|Fundus of patient with retinitis pigmentosa, mid stage Retinitis pigmentosa was first described in relation to the BEST1 gene in 2009 and was found to be associated with four different missense mutations in the BEST1 gene in people. All affected individuals experience a diminished response to light within their retina and may have changes in pigmentation, pale optic discs, fluid accumulation and decreased visual acuity.<ref name="Johnson_2017" />
All of the diseases above do not have any known treatments or cures. However, as of 2017, researchers are currently working on discovering treatments with stem cell transplants of the retinal pigment epithelium.<ref name="Johnson_2017" />{{clear}}
== References == {{reflist|33em}}
== Further reading == {{refbegin|33em}} * {{cite journal | vauthors = White K, Marquardt A, Weber BH | title = VMD2 mutations in vitelliform macular dystrophy (Best disease) and other maculopathies | journal = Human Mutation | volume = 15 | issue = 4 | pages = 301–8 | year = 2000 | pmid = 10737974 | doi = 10.1002/(SICI)1098-1004(200004)15:4<301::AID-HUMU1>3.0.CO;2-N | s2cid = 23807050 | doi-access = free }} * {{cite journal | vauthors = Nordström S, Barkman Y | title = Hereditary maculardegeneration (HMD) in 246 cases traced to one gene-source in central Sweden | journal = Hereditas | volume = 84 | issue = 2 | pages = 163–76 | date = February 1977 | pmid = 838599 | doi = 10.1111/j.1601-5223.1977.tb01394.x | doi-access =free }} * {{cite journal | vauthors = Forsman K, Graff C, Nordström S, Johansson K, Westermark E, Lundgren E, Gustavson KH, Wadelius C, Holmgren G | title = The gene for Best's macular dystrophy is located at 11q13 in a Swedish family | journal = Clinical Genetics | volume = 42 | issue = 3 | pages = 156–9 | date = September 1992 | pmid = 1395087 | doi = 10.1111/j.1399-0004.1992.tb03229.x | s2cid = 924428 }} * {{cite journal | vauthors = Stöhr H, Marquardt A, Rivera A, Cooper PR, Nowak NJ, Shows TB, Gerhard DS, Weber BH | title = A gene map of the Best's vitelliform macular dystrophy region in chromosome 11q12-q13.1 | journal = Genome Research | volume = 8 | issue = 1 | pages = 48–56 | date = January 1998 | pmid = 9445487 | pmc = 310689 | doi = 10.1101/gr.8.1.48 }} * {{cite journal | vauthors = Petrukhin K, Koisti MJ, Bakall B, Li W, Xie G, Marknell T, Sandgren O, Forsman K, Holmgren G, Andreasson S, Vujic M, Bergen AA, McGarty-Dugan V, Figueroa D, Austin CP, Metzker ML, Caskey CT, Wadelius C | title = Identification of the gene responsible for Best macular dystrophy | journal = Nature Genetics | volume = 19 | issue = 3 | pages = 241–7 | date = July 1998 | pmid = 9662395 | doi = 10.1038/915 | s2cid = 23334668 }} * {{cite journal | vauthors = Pennisi E | author-link=Elizabeth Pennisi | title = New gene found for inherited macular degeneration | journal = Science | volume = 281 | issue = 5373 | pages = 31 | date = July 1998 | pmid = 9679014 | doi = 10.1126/science.281.5373.31 | s2cid = 44271444 }} * {{cite journal | vauthors = Marquardt A, Stöhr H, Passmore LA, Krämer F, Rivera A, Weber BH | title = Mutations in a novel gene, VMD2, encoding a protein of unknown properties cause juvenile-onset vitelliform macular dystrophy (Best's disease) | journal = Human Molecular Genetics | volume = 7 | issue = 9 | pages = 1517–25 | date = September 1998 | pmid = 9700209 | doi = 10.1093/hmg/7.9.1517 | doi-access = free }} * {{cite journal | vauthors = Caldwell GM, Kakuk LE, Griesinger IB, Simpson SA, Nowak NJ, Small KW, Maumenee IH, Rosenfeld PJ, Sieving PA, Shows TB, Ayyagari R | title = Bestrophin gene mutations in patients with Best vitelliform macular dystrophy | journal = Genomics | volume = 58 | issue = 1 | pages = 98–101 | date = May 1999 | pmid = 10331951 | doi = 10.1006/geno.1999.5808 }} * {{cite journal | vauthors = Bakall B, Marknell T, Ingvast S, Koisti MJ, Sandgren O, Li W, Bergen AA, Andreasson S, Rosenberg T, Petrukhin K, Wadelius C | title = The mutation spectrum of the bestrophin protein--functional implications | journal = Human Genetics | volume = 104 | issue = 5 | pages = 383–9 | date = May 1999 | pmid = 10394929 | doi = 10.1007/s004390050972 | s2cid = 21255716 }} * {{cite journal | vauthors = Allikmets R, Seddon JM, Bernstein PS, Hutchinson A, Atkinson A, Sharma S, Gerrard B, Li W, Metzker ML, Wadelius C, Caskey CT, Dean M, Petrukhin K | title = Evaluation of the Best disease gene in patients with age-related macular degeneration and other maculopathies | journal = Human Genetics | volume = 104 | issue = 6 | pages = 449–53 | date = June 1999 | pmid = 10453731 | doi = 10.1007/s004390050986 | s2cid = 6214287 }} * {{cite journal | vauthors = Palomba G, Rozzo C, Angius A, Pierrottet CO, Orzalesi N, Pirastu M | title = A novel spontaneous missense mutation in VMD2 gene is a cause of a best macular dystrophy sporadic case | journal = American Journal of Ophthalmology | volume = 129 | issue = 2 | pages = 260–2 | date = February 2000 | pmid = 10682987 | doi = 10.1016/S0002-9394(99)00327-X }} * {{cite journal | vauthors = Lotery AJ, Namperumalsamy P, Jacobson SG, Weleber RG, Fishman GA, Musarella MA, Hoyt CS, Héon E, Levin A, Jan J, Lam B, Carr RE, Franklin A, Radha S, Andorf JL, Sheffield VC, Stone EM | title = Mutation analysis of 3 genes in patients with Leber congenital amaurosis | journal = Archives of Ophthalmology | volume = 118 | issue = 4 | pages = 538–43 | date = April 2000 | pmid = 10766140 | doi = 10.1001/archopht.118.4.538 | author2-link = P. Namperumalsamy | doi-access = free }} * {{cite journal | vauthors = Lotery AJ, Munier FL, Fishman GA, Weleber RG, Jacobson SG, Affatigato LM, Nichols BE, Schorderet DF, Sheffield VC, Stone EM | title = Allelic variation in the VMD2 gene in best disease and age-related macular degeneration | journal = Investigative Ophthalmology & Visual Science | volume = 41 | issue = 6 | pages = 1291–6 | date = May 2000 | pmid = 10798642 }} * {{cite journal | vauthors = Krämer F, White K, Pauleikhoff D, Gehrig A, Passmore L, Rivera A, Rudolph G, Kellner U, Andrassi M, Lorenz B, Rohrschneider K, Blankenagel A, Jurklies B, Schilling H, Schütt F, Holz FG, Weber BH | title = 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 | journal = European Journal of Human Genetics | volume = 8 | issue = 4 | pages = 286–92 | date = April 2000 | pmid = 10854112 | doi = 10.1038/sj.ejhg.5200447 | doi-access = free }} * {{cite journal | vauthors = Marmorstein AD, Marmorstein LY, Rayborn M, Wang X, Hollyfield JG, Petrukhin K | title = Bestrophin, the product of the Best vitelliform macular dystrophy gene (VMD2), localizes to the basolateral plasma membrane of the retinal pigment epithelium | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 23 | pages = 12758–63 | date = November 2000 | pmid = 11050159 | pmc = 18837 | doi = 10.1073/pnas.220402097 | bibcode = 2000PNAS...9712758M | doi-access = free }} * {{cite journal | vauthors = Marchant D, Gogat K, Boutboul S, Péquignot M, Sternberg C, Dureau P, Roche O, Uteza Y, Hache JC, Puech B, Puech V, Dumur V, Mouillon M, Munier FL, Schorderet DF, Marsac C, Dufier JL, Abitbol M | title = Identification of novel VMD2 gene mutations in patients with best vitelliform macular dystrophy | journal = Human Mutation | volume = 17 | issue = 3 | pages = 235 | date = March 2001 | pmid = 11241846 | doi = 10.1002/humu.9 | s2cid = 16128731 | doi-access = free }} * {{cite journal | vauthors = Eksandh L, Bakall B, Bauer B, Wadelius C, Andréasson S | title = Best's vitelliform macular dystrophy caused by a new mutation (Val89Ala) in the VMD2 gene | journal = Ophthalmic Genetics | volume = 22 | issue = 2 | pages = 107–15 | date = June 2001 | pmid = 11449320 | doi = 10.1076/opge.22.2.107.2226 | s2cid = 7035792 }} * {{cite journal | vauthors = Sun H, Tsunenari T, Yau KW, Nathans J | title = The vitelliform macular dystrophy protein defines a new family of chloride channels | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 6 | pages = 4008–13 | date = March 2002 | pmid = 11904445 | pmc = 122639 | doi = 10.1073/pnas.052692999 | bibcode = 2002PNAS...99.4008S | doi-access = free }} * {{cite journal | vauthors = Xiao Q, Yu K, Cui YY, Hartzell HC | title = Dysregulation of human bestrophin-1 by ceramide-induced dephosphorylation | journal = The Journal of Physiology | volume = 587 | issue = Pt 18 | pages = 4379–91 | date = September 2009 | pmid = 19635817 | pmc = 2766645 | doi = 10.1113/jphysiol.2009.176800 }} * {{cite journal | vauthors = Xiao Q, Prussia A, Yu K, Cui YY, Hartzell HC | title = Regulation of bestrophin Cl channels by calcium: role of the C terminus | journal = The Journal of General Physiology | volume = 132 | issue = 6 | pages = 681–92 | date = December 2008 | pmid = 19029375 | pmc = 2585866 | doi = 10.1085/jgp.200810056 }} {{refend}}
== External links == * [https://www.ncbi.nlm.nih.gov/books/NBK1417/ GeneReviews/NCBI/NIH/UW entry on Retinitis Pigmentosa Overview] * {{UCSC gene info|BEST1}}
{{NLM content}} {{Ion channels|g4}}
Category:Ion channels