Bestrophin 1

Bestrophin 1
Identifiers
Symbols	BEST1 ; ARB; BEST; BMD; RP50; TU15B; VMD2
External IDs	OMIM: 607854 MGI: 1346332 HomoloGene: 37895 GeneCards: BEST1 Gene
Gene ontology Molecular function • chloride channel activity Cellular component • cytosol • plasma membrane • membrane • integral component of membrane • basolateral plasma membrane • chloride channel complex Biological process • chloride transport • visual perception • transepithelial chloride transport • ion transmembrane transport • detection of light stimulus involved in visual perception • regulation of calcium ion transport • transmembrane transport • chloride transmembrane transport Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	7439	24115
Ensembl	ENSG00000167995	ENSMUSG00000037418
UniProt	O76090	O88870
RefSeq (mRNA)	NM_001139443	NM_011913
RefSeq (protein)	NP_001132915	NP_036043
Location (UCSC)	Chr 11: 61.95 – 61.97 Mb	Chr 19: 9.99 – 10 Mb
PubMed search

Bestrophin-1 is a protein that in humans is encoded by the BEST1 gene.^[1][2][3]

It can be associated with Vitelliform macular dystrophy.

Function

BEST1 belongs to the bestrophin family of calcium-activated anion channels, which includes BEST2, BEST3, and BEST4. 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. Bestrophins are believed to function as chloride channels that may also serve as regulators of intracellular calcium signalling.^[4]

Bestrophin 1 was shown to be permeable for chloride, thiocyanate, bicarbonate, glutamate, and GABA. Bestrophin 1-mediated GABA release has recently been demonstrated to be responsible for tonic inhibition in cerebellar granule cells,^[5] and has been linked to the pathology of Alzheimer's disease.^[6]

Gene structure

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.^[3][7][8]

BEST1 has been shown by two independent studies to be regulated by Microphthalmia-associated transcription factor.^[9][10]

Interactions

Bestrophin 1 has been shown to interact with PPP2CA.^[11]

Antagonists

• Verteporfin ^[12]

References

1. Stone EM, Nichols BE, Streb LM, Kimura AE, Sheffield VC (Jun 1993). "Genetic linkage of vitelliform macular degeneration (Best's disease) to chromosome 11q13". Nat Genet 1 (4): 246–50. doi:10.1038/ng0792-246. PMID 1302019.
2. Barro Soria R, Spitzner M, Schreiber R, Kunzelmann K (Sep 2006). "Bestrophin 1 enables Ca²⁺ activated Cl⁻ conductance in epithelia". J Biol Chem 284 (43): 29405–12. doi:10.1074/jbc.M605716200. PMC 2785573. PMID 17003041.
3. "Entrez Gene: BEST1 bestrophin 1".
4. 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". Physiol. Rev. 88 (2): 639–72. doi:10.1152/physrev.00022.2007. PMID 18391176.
5. Lee S, Yoon BE, Berglund K, Oh SJ, Park H, Shin HS, Augustine GJ, Lee CJ (November 2010). "Channel-mediated tonic GABA release from glia". Science 330 (6005): 790–6. doi:10.1126/science.1184334. PMID 20929730.
6. Jo, Seonmi (2014). "GABA from reactive astrocytes impairs memory in mouse models of Alzheimer's disease". Nature Medicine 20 (8): 886–896. doi:10.1038/nm.3639.
7. Stöhr H, Marquardt A, Nanda I, Schmid M, Weber BH (April 2002). "Three novel human VMD2-like genes are members of the evolutionary highly conserved RFP-TM family". Eur. J. Hum. Genet. 10 (4): 281–4. doi:10.1038/sj.ejhg.5200796. PMID 12032738.
8. Tsunenari T, Sun H, Williams J, Cahill H, Smallwood P, Yau KW, Nathans J (October 2003). "Structure-function analysis of the bestrophin family of anion channels". J. Biol. Chem. 278 (42): 41114–25. doi:10.1074/jbc.M306150200. PMC 2885917. PMID 12907679.
9. Esumi N, Kachi S, Campochiaro PA, Zack DJ (2007). "VMD2 promoter requires two proximal E-box sites for its activity in vivo and is regulated by the MITF-TFE family". J. Biol. Chem. 282 (3): 1838–50. doi:10.1074/jbc.M609517200. PMID 17085443.
10. Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, Valgeirsdottir S, Bergsteinsdottir K, Schepsky A, Dummer R, Steingrimsson E (2008). "Novel MITF targets identified using a two-step DNA microarray strategy". Pigment Cell Melanoma Res. 21 (6): 665–76. doi:10.1111/j.1755-148X.2008.00505.x. PMID 19067971.
11. Marmorstein LY, McLaughlin PJ, Stanton JB, Yan L, Crabb JW, Marmorstein AD (2002). "Bestrophin interacts physically and functionally with protein phosphatase 2A". J. Biol. Chem. 277 (34): 30591–7. doi:10.1074/jbc.M204269200. PMID 12058047.
12. Rao PR. Identification of novel selective antagonists for Bestrophin-1 protein by homology modeling and molecular docking. International Journal of Pharmacy and Pharmaceutical Sciences 2012; 4(S4):195-200.

Further reading

• White K, Marquardt A, Weber BH (2000). "VMD2 mutations in vitelliform macular dystrophy (Best disease) and other maculopathies". Hum. Mutat. 15 (4): 301–8. doi:10.1002/(SICI)1098-1004(200004)15:4<301::AID-HUMU1>3.0.CO;2-N. PMID 10737974.
• Nordström S, Barkman Y (1977). "Hereditary maculardegeneration (HMD) in 246 cases traced to one gene-source in central Sweden". Hereditas 84 (2): 163–76. doi:10.1111/j.1601-5223.1977.tb01394.x. PMID 838599.
• Forsman K, Graff C, Nordström S; et al. (1992). "The gene for Best's macular dystrophy is located at 11q13 in a Swedish family". Clin. Genet. 42 (3): 156–9. doi:10.1111/j.1399-0004.1992.tb03229.x. PMID 1395087.
• Stöhr H, Marquardt A, Rivera A; et al. (1998). "A gene map of the Best's vitelliform macular dystrophy region in chromosome 11q12-q13.1". Genome Res. 8 (1): 48–56. doi:10.1101/gr.8.1.48. PMC 310689. PMID 9445487.
• Petrukhin K, Koisti MJ, Bakall B; et al. (1998). "Identification of the gene responsible for Best macular dystrophy". Nat. Genet. 19 (3): 241–7. doi:10.1038/915. PMID 9662395.
• Pennisi E (1998). "New gene found for inherited macular degeneration". Science 281 (5373): 31. doi:10.1126/science.281.5373.31. PMID 9679014.
• Marquardt A, Stöhr H, Passmore LA; et al. (1998). "Mutations in a novel gene, VMD2, encoding a protein of unknown properties cause juvenile-onset vitelliform macular dystrophy (Best's disease)". Hum. Mol. Genet. 7 (9): 1517–25. doi:10.1093/hmg/7.9.1517. PMID 9700209.
• Caldwell GM, Kakuk LE, Griesinger IB; et al. (1999). "Bestrophin gene mutations in patients with Best vitelliform macular dystrophy". Genomics 58 (1): 98–101. doi:10.1006/geno.1999.5808. PMID 10331951.
• Bakall B, Marknell T, Ingvast S; et al. (1999). "The mutation spectrum of the bestrophin protein--functional implications". Hum. Genet. 104 (5): 383–9. doi:10.1007/s004390050972. PMID 10394929.
• Allikmets R, Seddon JM, Bernstein PS; et al. (1999). "Evaluation of the Best disease gene in patients with age-related macular degeneration and other maculopathies". Hum. Genet. 104 (6): 449–53. doi:10.1007/s004390050986. PMID 10453731.
• Palomba G, Rozzo C, Angius A; et al. (2000). "A novel spontaneous missense mutation in VMD2 gene is a cause of a best macular dystrophy sporadic case". Am. J. Ophthalmol. 129 (2): 260–2. doi:10.1016/S0002-9394(99)00327-X. PMID 10682987.
• Lotery AJ, Namperumalsamy P, Jacobson SG; et al. (2000). "Mutation analysis of 3 genes in patients with Leber congenital amaurosis". Arch. Ophthalmol. 118 (4): 538–43. doi:10.1001/archopht.118.4.538. PMID 10766140.
• Lotery AJ, Munier FL, Fishman GA; et al. (2000). "Allelic variation in the VMD2 gene in best disease and age-related macular degeneration". Invest. Ophthalmol. Vis. Sci. 41 (6): 1291–6. PMID 10798642.
• Krämer F, White K, Pauleikhoff D; et al. (2000). "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". Eur. J. Hum. Genet. 8 (4): 286–92. doi:10.1038/sj.ejhg.5200447. PMID 10854112.
• Marmorstein AD, Marmorstein LY, Rayborn M; et al. (2001). "Bestrophin, the product of the Best vitelliform macular dystrophy gene (VMD2), localizes to the basolateral plasma membrane of the retinal pigment epithelium". Proc. Natl. Acad. Sci. U.S.A. 97 (23): 12758–63. doi:10.1073/pnas.220402097. PMC 18837. PMID 11050159.
• Marchant D, Gogat K, Boutboul S; et al. (2001). "Identification of novel VMD2 gene mutations in patients with best vitelliform macular dystrophy". Hum. Mutat. 17 (3): 235. doi:10.1002/humu.9. PMID 11241846.
• Eksandh L, Bakall B, Bauer B; et al. (2001). "Best's vitelliform macular dystrophy caused by a new mutation (Val89Ala) in the VMD2 gene". Ophthalmic Genet. 22 (2): 107–15. doi:10.1076/opge.22.2.107.2226. PMID 11449320.
• Sun H, Tsunenari T, Yau KW, Nathans J (2002). "The vitelliform macular dystrophy protein defines a new family of chloride channels". Proc. Natl. Acad. Sci. U.S.A. 99 (6): 4008–13. doi:10.1073/pnas.052692999. PMC 122639. PMID 11904445.
• Xiao Q, Yu K, Cui YY, Hartzell HC (2009). "Dysregulation of human bestrophin-1 by ceramide-induced dephosphorylation". J Physiol. 587 (18): 4379–91. doi:10.1113/jphysiol.2009.176800. PMC 2766645. PMID 19635817.
• Xiao Q, Prussia A, Yu K, Cui YY, Hartzell HC (2008). "Regulation of bestrophin Cl channels by calcium: role of the C terminus". J Gen Physiol. 132 (6): 681–92. doi:10.1085/jgp.200810056. PMC 2585866. PMID 19029375.

External links

• GeneReviews/NCBI/NIH/UW entry on Retinitis Pigmentosa Overview

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