Bestrophin 1: Difference between revisions

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[[File:Bestrophin-1_5T5N_Xray_Cystallography.png|link=https://en.wikipedia.org/wiki/File:Bestrophin-1_5T5N_Xray_Cystallography.png|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}}
{{PBB_Controls
'''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/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7439| accessdate = }}</ref>
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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 [[Retinal degeneration (rhodopsin mutation)|degenerative retinal]] diseases.<ref name="Johnson_2017" />
{{GNF_Protein_box
| image = 
| image_source = 
| PDB =
| Name = Bestrophin 1
| HGNCid = 12703
| Symbol = BEST1
| AltSymbols =; BMD; BEST; TU15B; VMD2
| OMIM = 607854
| ECnumber = 
| Homologene = 37895
| MGIid = 1346332
| GeneAtlas_image1 = PBB_GE_BEST1_207671_s_at_tn.png
| Function = {{GNF_GO|id=GO:0005216 |text = ion channel activity}} {{GNF_GO|id=GO:0005254 |text = chloride channel activity}} {{GNF_GO|id=GO:0005509 |text = calcium ion binding}} {{GNF_GO|id=GO:0031404 |text = chloride ion binding}}
| Component = {{GNF_GO|id=GO:0005624 |text = membrane fraction}} {{GNF_GO|id=GO:0016020 |text = membrane}} {{GNF_GO|id=GO:0016021 |text = integral to membrane}} {{GNF_GO|id=GO:0016323 |text = basolateral plasma membrane}}
| Process = {{GNF_GO|id=GO:0006811 |text = ion transport}} {{GNF_GO|id=GO:0007601 |text = visual perception}} {{GNF_GO|id=GO:0050896 |text = response to stimulus}}  
  | Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 7439
    | Hs_Ensembl = ENSG00000167995
    | Hs_RefseqProtein = NP_004174
    | Hs_RefseqmRNA = NM_004183
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 11
    | Hs_GenLoc_start = 61474408
    | Hs_GenLoc_end = 61488509
    | Hs_Uniprot = O76090
    | Mm_EntrezGene = 24115
    | Mm_Ensembl = ENSMUSG00000037418
    | Mm_RefseqmRNA = XM_980943
    | Mm_RefseqProtein = XP_986037
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 19
    | Mm_GenLoc_start = 10052219
    | Mm_GenLoc_end = 10064259
    | Mm_Uniprot = O88870
  }}
}}
'''Bestrophin 1''', also known as '''BEST1''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: BEST1 bestrophin 1| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7439| accessdate = }}</ref>


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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 [[Ion|anion]] channels, each of which has a unique tissue distribution throughout the body. Specifically, the BEST1 gene on [[Chromosome 11 (human)|chromosome 11q13]] encodes the Bestrophin-1 protein in humans whose expression is highest in the [[retina]].<ref name="Johnson_2017"/>
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==References==
== Structure ==
{{reflist|2}}
 
==Further reading==
=== Gene ===
{{refbegin | 2}}
 
{{PBB_Further_reading
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" />
| citations =
 
*{{cite journal  | author=White K, Marquardt A, Weber BH |title=VMD2 mutations in vitelliform macular dystrophy (Best disease) and other maculopathies. |journal=Hum. Mutat. |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 }}
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 }}</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 | department = primary }}</ref>
*{{cite journal | author=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 |year= 1977 |pmid= 838599 |doi= }}
 
*{{cite journal | author=Stone EM, Nichols BE, Streb LM, ''et al.'' |title=Genetic linkage of vitelliform macular degeneration (Best's disease) to chromosome 11q13. |journal=Nat. Genet. |volume=1 |issue= 4 |pages= 246-50 |year= 1993 |pmid= 1302019 |doi= 10.1038/ng0792-246 }}
=== Protein ===
*{{cite journal  | author=Forsman K, Graff C, Nordström S, ''et al.'' |title=The gene for Best's macular dystrophy is located at 11q13 in a Swedish family. |journal=Clin. Genet. |volume=42 |issue= 3 |pages= 156-9 |year= 1992 |pmid= 1395087 |doi=  }}
 
*{{cite journal  | author=Stöhr H, Marquardt A, Rivera A, ''et al.'' |title=A gene map of the Best's vitelliform macular dystrophy region in chromosome 11q12-q13.1. |journal=Genome Res. |volume=8 |issue= 1 |pages= 48-56 |year= 1998 |pmid= 9445487 |doi=  }}
Bestrophin-1 is an integral membrane protein found primarily in the [[retinal pigment epithelium]] (RPE) of the eye.<ref name="Strauss_2012">{{cite journal | vauthors = Strauss O, Neussert R, Müller C, Milenkovic VM | title = A potential cytosolic function of bestrophin-1 | journal = Advances in Experimental Medicine and Biology | volume = 723 | issue = | 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|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 acid]]s and both [[N-terminus|N-]] and the [[C-terminus|C-termini]] are located within the cell.
*{{cite journal | author=Petrukhin K, Koisti MJ, Bakall B, ''et al.'' |title=Identification of the gene responsible for Best macular dystrophy. |journal=Nat. Genet. |volume=19 |issue= 3 |pages= 241-7 |year= 1998 |pmid= 9662395 |doi= 10.1038/915 }}
[[File:Bestrophin 1 Side edge centered.png|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]]
*{{cite journal | author=Pennisi E |title=New gene found for inherited macular degeneration. |journal=Science |volume=281 |issue= 5373 |pages= 31 |year= 1998 |pmid= 9679014 |doi= }}
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 protein|transmembrane]] domain containing a high content of [[Aromaticity|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 [[Chemical polarity|nonpolar]], [[Hydrophobe|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 change]]s caused by calcium binding at the C-terminus directly following the last transmembrane domain.<ref name="Johnson_2017" /><ref name="Xiao_20102"/>
*{{cite journal  | author=Marquardt A, Stöhr H, Passmore LA, ''et al.'' |title=Mutations in a novel gene, VMD2, encoding a protein of unknown properties cause juvenile-onset vitelliform macular dystrophy (Best's disease). |journal=Hum. Mol. Genet. |volume=7 |issue= 9 |pages= 1517-25 |year= 1998 |pmid= 9700209 |doi=  }}
 
*{{cite journal  | author=Caldwell GM, Kakuk LE, Griesinger IB, ''et al.'' |title=Bestrophin gene mutations in patients with Best vitelliform macular dystrophy. |journal=Genomics |volume=58 |issue= 1 |pages= 98-101 |year= 1999 |pmid= 10331951 |doi= 10.1006/geno.1999.5808 }}
== Tissue and subcellular distribution ==
*{{cite journal  | author=Bakall B, Marknell T, Ingvast S, ''et al.'' |title=The mutation spectrum of the bestrophin protein--functional implications. |journal=Hum. Genet. |volume=104 |issue= 5 |pages= 383-9 |year= 1999 |pmid= 10394929 |doi= }}
 
*{{cite journal  | author=Allikmets R, Seddon JM, Bernstein PS, ''et al.'' |title=Evaluation of the Best disease gene in patients with age-related macular degeneration and other maculopathies. |journal=Hum. Genet. |volume=104 |issue= 6 |pages= 449-53 |year= 1999 |pmid= 10453731 |doi=  }}
The location of expression of the BEST1 gene is essential for protein functioning and mislocalization is often connected to a variety of [[retina]]l [[Degenerative disease|degenerative]] diseases. The BEST1 gene expresses the Best1 protein primarily in the [[cytosol]] of the retinal pigment epithelium. The protein is typically contained in [[Vesicle (biology and chemistry)|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 [[STIM1|Stim-1]]. Calcium ion involvement in the [[Active transport|countertransport]] of chloride ions also supports the idea that Best1 is involved in forming calcium stores within the cell.<ref name="Strauss_2012"/>
*{{cite journal  | author=Palomba G, Rozzo C, Angius A, ''et al.'' |title=A novel spontaneous missense mutation in VMD2 gene is a cause of a best macular dystrophy sporadic case. |journal=Am. J. Ophthalmol. |volume=129 |issue= 2 |pages= 260-2 |year= 2000 |pmid= 10682987 |doi= }}
 
*{{cite journal  | author=Lotery AJ, Namperumalsamy P, Jacobson SG, ''et al.'' |title=Mutation analysis of 3 genes in patients with Leber congenital amaurosis. |journal=Arch. Ophthalmol. |volume=118 |issue= 4 |pages= 538-43 |year= 2000 |pmid= 10766140 |doi= }}
== Function ==
*{{cite journal  | author=Lotery AJ, Munier FL, Fishman GA, ''et al.'' |title=Allelic variation in the VMD2 gene in best disease and age-related macular degeneration. |journal=Invest. Ophthalmol. Vis. Sci. |volume=41 |issue= 6 |pages= 1291-6 |year= 2000 |pmid= 10798642 |doi= }}
 
*{{cite journal  | author=Krämer F, White K, Pauleikhoff D, ''et al.'' |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=Eur. J. Hum. Genet. |volume=8 |issue= 4 |pages= 286-92 |year= 2000 |pmid= 10854112 |doi= 10.1038/sj.ejhg.5200447 }}
Best1 primarily functions as an intracellular calcium-activated chloride channel on the cellular membrane that is not [[Voltage-gated ion channel|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.
*{{cite journal  | author=Marmorstein AD, Marmorstein LY, Rayborn M, ''et al.'' |title=Bestrophin, the product of the Best vitelliform macular dystrophy gene (VMD2), localizes to the basolateral plasma membrane of the retinal pigment epithelium. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=97 |issue= 23 |pages= 12758-63 |year= 2001 |pmid= 11050159 |doi= 10.1073/pnas.220402097 }}
 
*{{cite journal | author=Marchant D, Gogat K, Boutboul S, ''et al.'' |title=Identification of novel VMD2 gene mutations in patients with best vitelliform macular dystrophy. |journal=Hum. Mutat. |volume=17 |issue= 3 |pages= 235 |year= 2001 |pmid= 11241846 |doi= 10.1002/humu.9 }}
==Diseases ==
*{{cite journal | author=Eksandh L, Bakall B, Bauer B, ''et al.'' |title=Best's vitelliform macular dystrophy caused by a new mutation (Val89Ala) in the VMD2 gene. |journal=Ophthalmic Genet. |volume=22 |issue= 2 |pages= 107-15 |year= 2001 |pmid= 11449320 |doi= }}
 
*{{cite journal | author=Sun H, Tsunenari T, Yau KW, Nathans J |title=The vitelliform macular dystrophy protein defines a new family of chloride channels. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 6 |pages= 4008-13 |year= 2002 |pmid= 11904445 |doi= 10.1073/pnas.052692999 }}
=== Best’s vitelliform macular dystrophy (BVMD) ===
}}
[[File:Lipofuscin_neuro.jpg|link=https://en.wikipedia.org/wiki/File:Lipofuscin_neuro.jpg|thumb|Lipofuscin (lipid residual from lysosome digestion) in a human neuron. Representative of what may occur in the eye 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) [[lesion]]s 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 [[Cell membrane|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 [[Dominance (genetics)|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 mutation]]s; 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 | date = 2014 | publisher = Springer | location = New York | isbn = 978-1-4614-3209-8 | doi = 10.1007/978-1-4614-3209-8_15 | pages = 113–119 | department = review }}</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"/>
 
=== 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 [[Dominance (genetics)|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 [[Noncoding DNA|non-coding regions]].<ref name="Johnson_2017" />
 
[[File:Cataract in human eye.png|thumb|Cataract in human eye, potentially caused by autosomal dominant vitreoretinochoroidpathy.]]
 
=== Autosomal dominant vitreoretinochoroidopathy  ===
Autosomal dominant vitreoretinochoroidpathy 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 [[cataract]]s are also likely.<ref name="Johnson_2017" />
 
=== Retinitis pigmentosa (RP) ===
[[File:Fundus_of_patient_with_retinitis_pigmentosa,_mid_stage.jpg|link=https://en.wikipedia.org/wiki/File:Fundus_of_patient_with_retinitis_pigmentosa,_mid_stage.jpg|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 disc]]s, 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 [[Hematopoietic stem cell transplantation|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 }}
* {{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 }}
* {{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 }}
* {{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 }}
* {{cite journal | vauthors = Pennisi E | 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 }}
* {{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 }}
* {{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 }}
* {{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 }}
* {{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 }}
* {{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 | doi =  }}
* {{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 }}
* {{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 }}
* {{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 }}
* {{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 }}
* {{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 }}
* {{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}}
{{refend}}


{{protein-stub}}
== 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]]

Latest revision as of 17:32, 16 March 2018

File:Bestrophin-1 5T5N Xray Cystallography.png
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.
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Identifiers
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SpeciesHumanMouse
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View/Edit Human

Bestrophin-1 (Best1) is a protein that, in humans, is encoded by the BEST1 gene (RPD ID - 5T5N/4RDQ).[1]

The bestrophin family of proteins comprises four evolutionary related genes (BEST1, BEST2, BEST3, and BEST4) that code for integral membrane proteins.[2] This family was first identified in humans by linking a BEST1 mutation with Best vitelliform macular dystrophy (BVMD).[3] Mutations in the BEST1 gene have been identified as the primary cause for at least five different degenerative retinal diseases.[3]

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.[3]

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.[1]

BEST1 has been shown by two independent studies to be regulated by Microphthalmia-associated transcription factor.[4][5]

Protein

Bestrophin-1 is an integral membrane protein found primarily in the retinal pigment epithelium (RPE) of the eye.[6] 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.[6][3] Bestrophin-1 consists of 585 amino acids and both N- and the C-termini are located within the cell.

File:Bestrophin 1 Side edge centered.png
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.[3][7][8] 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.[3][8]

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.[6]

Function

Best1 primarily functions as an intracellular calcium-activated chloride channel on the cellular membrane that is not voltage-dependent.[2][6][8] More recently Best1 has been shown to act as a volume-regulating anion channel.

Diseases

Best’s vitelliform macular dystrophy (BVMD)

File:Lipofuscin neuro.jpg
Lipofuscin (lipid residual from lysosome digestion) in a human neuron. Representative of what may occur in the eye 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.[2][6] 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.[6] 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.[3][6] 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.[3] 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.[9] To date, over 100 disease-causing mutations have been related to BVMD as well as a number of other degenerative retinal diseases.[8]

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.[3]

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.[3]

Cataract in human eye, potentially caused by autosomal dominant vitreoretinochoroidpathy.

Autosomal dominant vitreoretinochoroidopathy

Autosomal dominant vitreoretinochoroidpathy 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.[3]

Retinitis pigmentosa (RP)

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.[3]

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.[3]

References

  1. ↑ 1.0 1.1 "Entrez Gene: BEST1 bestrophin 1".
  2. ↑ 2.0 2.1 2.2 Kunzelmann K (September 2015). "TMEM16, LRRC8A, bestrophin: chloride channels controlled by Ca(2+) and cell volume". review. Trends in Biochemical Sciences. 40 (9): 535–43. doi:10.1016/j.tibs.2015.07.005. PMID 26254230.
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 Johnson AA, Guziewicz KE, Lee CJ, Kalathur RC, Pulido JS, Marmorstein LY, Marmorstein AD (January 2017). "Bestrophin 1 and retinal disease". review. Progress in Retinal and Eye Research. 58: 45–69. doi:10.1016/j.preteyeres.2017.01.006. PMC 5600499. PMID 28153808.
  4. ↑ Esumi N, Kachi S, Campochiaro PA, Zack DJ (January 2007). "VMD2 promoter requires two proximal E-box sites for its activity in vivo and is regulated by the MITF-TFE family". primary. The Journal of Biological Chemistry. 282 (3): 1838–50. doi:10.1074/jbc.M609517200. PMID 17085443.
  5. ↑ Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, Valgeirsdottir S, Bergsteinsdottir K, Schepsky A, Dummer R, Steingrimsson E (December 2008). "Novel MITF targets identified using a two-step DNA microarray strategy". primary. Pigment Cell & Melanoma Research. 21 (6): 665–76. doi:10.1111/j.1755-148X.2008.00505.x. PMID 19067971.
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 Strauss O, Neussert R, Müller C, Milenkovic VM (2012). "A potential cytosolic function of bestrophin-1". review. Advances in Experimental Medicine and Biology. Advances in Experimental Medicine and Biology. 723: 603–10. doi:10.1007/978-1-4614-0631-0_77. ISBN 978-1-4614-0630-3. PMID 22183384.
  7. ↑ Hartzell HC, Qu Z, Yu K, Xiao Q, Chien LT (April 2008). "Molecular physiology of bestrophins: multifunctional membrane proteins linked to best disease and other retinopathies". review. Physiological Reviews. 88 (2): 639–72. doi:10.1152/physrev.00022.2007. PMID 18391176.
  8. ↑ 8.0 8.1 8.2 8.3 Xiao Q, Hartzell HC, Yu K (July 2010). "Bestrophins and retinopathies". review. Pflügers Archiv. 460 (2): 559–69. doi:10.1007/s00424-010-0821-5. PMC 2893225. PMID 20349192.
  9. ↑ Olaf S, Müller C, Reichhart N, Tamm ER, Gomez NM (2014). "The Role of Bestrophin-1 in Intracellular Ca2+ Signaling". In Ash J, Grimm C, Hollyfield JG, Anderson RE, LaVail NM, Rickman CB. Retinal Degenerative Diseases: Mechanisms and Experimental Therapy. review. New York: Springer. pp. 113–119. doi:10.1007/978-1-4614-3209-8_15. ISBN 978-1-4614-3209-8.

Further reading

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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