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.
Bestrophin-1 (Best1) is aprotein that, in humans, is encoded by theBEST1gene (RPD ID - 5T5N/4RDQ).[5]
The bestrophin family of proteins comprises four evolutionary related genes (BEST1,BEST2, BEST3, and BEST4) that code forintegral membrane proteins.[6] This family was first identified in humans by linking a BEST1mutation with Bestvitelliform macular dystrophy (BVMD).[7] Mutations in the BEST1 gene have been identified as the primary cause for at least five differentdegenerative retinal diseases.[7]
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-activatedanion channels, each of which has a unique tissue distribution throughout the body. Specifically, the BEST1 gene onchromosome 11q13 encodes the Bestrophin-1 protein in humans whose expression is highest in theretina.[7]
The bestrophin genes share a conserved gene structure, with almost identical sizes of the 8 RFP-TM domain-encoding exons and highly conservedexon-intron boundaries. Each of the four bestrophin genes has a unique3-prime end of variable length.[5]
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 secondtransmembrane domain containing a high content ofaromatic residues, including an invariant arg-phe-pro (RFP) motif.[7][11][12] The pore is lined with variousnonpolar,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 toconformational changes caused by calcium binding at the C-terminus directly following the last transmembrane domain.[7][12]
The location of expression of the BEST1 gene is essential for protein functioning and mislocalization is often connected to a variety ofretinaldegenerative diseases. The BEST1 gene expresses the Best1 protein primarily in thecytosol of the retinal pigment epithelium. The protein is typically contained invesicles near the cellular membrane. There is also research to support that the Best1 protein is localized and produced in theendoplasmic reticulum (intracellularorganelle involved in protein and lipid synthesis). Best1 is typically expressed with other proteins also synthesized in theendoplasmic reticulum, such ascalreticulin,calnexin andStim-1. Calcium ion involvement in thecountertransport of chloride ions also supports the idea that Best1 is involved in forming calcium stores within the cell.[10]
Best1 primarily functions as an intracellular calcium-activated chloride channel on the cellular membrane that is notvoltage-dependent.[6][10][12] More recently Best1 has been shown to act as a volume-regulating anion channel.
Lipofuscin (lipid residual from lysosome digestion) in a human neuron. Representative of what may occur in the eye in people affected by BMVD.
Best'svitelliform macular dystrophy (BVMD) is one of the most common Best1-associated diseases. BVMD typically becomes noticeable in children and is represented by the buildup oflipofuscin (lipid residuals)lesions in the eye.[6][10] Diagnosis normally follows an abnormalelectrooculogram in which decreased activation of calcium channels in thebasolateral 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.[10] Although BVMD is anautosomal dominant form of macular dystrophy, expressivity varies within and between affected families although the overwhelming majority of affected families come from northern European descent.[7][10] Typically, people with this condition experience five progressively worsening stages, though timing and severity varies greatly. BVMD is often caused by the singlemissense mutations; however, amino acid deletions have also been identified.[7] 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.[13] To date, over 100 disease-causing mutations have been related to BVMD as well as a number of other degenerative retinal diseases.[12]
Adult-onsetvitelliform 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 byPRPH2 mutations. AVMD usually involves less vision loss than BVMD and cases do not usually run in families.[7]
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 isautosomal recessive, indicating that both alleles of the BEST1 gene must be mutated. Vitelliform lesions are often present and some cases involve cystoidmacular 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 innon-coding regions.[7]
Cataract in human eye, potentially caused by autosomal dominant vitreoretinochoroidopathy.
Autosomal dominant vitreoretinochoroidopathy was first identified in 1982 and presents itself in both eyes with decreases inperipheral vision due to excessive fluid and changes in eye retinal pigmentation. Early onsetcataracts are also likely.[7]
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, paleoptic discs, fluid accumulation and decreasedvisual acuity.[7]
All of the diseases above do not have any known treatments or cures. However, as of 2017, researchers are currently working on discovering treatments withstem cell transplants of the retinal pigment epithelium.[7]
^abcKunzelmann 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.PMID26254230.
^abcdefgStrauss O, Neussert R, Müller C, Milenkovic VM (2012). "A potential cytosolic function of bestrophin-1".Retinal Degenerative Diseases. review. Advances in Experimental Medicine and Biology. Vol. 723. pp. 603–10.doi:10.1007/978-1-4614-0631-0_77.ISBN978-1-4614-0630-3.PMID22183384.
^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.PMID18391176.
^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 (eds.).Retinal Degenerative Diseases: Mechanisms and Experimental Therapy. review. Advances in Experimental Medicine and Biology. Vol. 801. New York: Springer. pp. 113–119.doi:10.1007/978-1-4614-3209-8_15.ISBN978-1-4614-3209-8.PMID24664688.
Forsman K, Graff C, Nordström S, Johansson K, Westermark E, Lundgren E, Gustavson KH, Wadelius C, Holmgren G (September 1992). "The gene for Best's macular dystrophy is located at 11q13 in a Swedish family".Clinical Genetics.42 (3):156–9.doi:10.1111/j.1399-0004.1992.tb03229.x.PMID1395087.S2CID924428.
Caldwell GM, Kakuk LE, Griesinger IB, Simpson SA, Nowak NJ, Small KW, Maumenee IH, Rosenfeld PJ, Sieving PA, Shows TB, Ayyagari R (May 1999). "Bestrophin gene mutations in patients with Best vitelliform macular dystrophy".Genomics.58 (1):98–101.doi:10.1006/geno.1999.5808.PMID10331951.
Bakall B, Marknell T, Ingvast S, Koisti MJ, Sandgren O, Li W, Bergen AA, Andreasson S, Rosenberg T, Petrukhin K, Wadelius C (May 1999). "The mutation spectrum of the bestrophin protein--functional implications".Human Genetics.104 (5):383–9.doi:10.1007/s004390050972.PMID10394929.S2CID21255716.
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 (June 1999). "Evaluation of the Best disease gene in patients with age-related macular degeneration and other maculopathies".Human Genetics.104 (6):449–53.doi:10.1007/s004390050986.PMID10453731.S2CID6214287.
Palomba G, Rozzo C, Angius A, Pierrottet CO, Orzalesi N, Pirastu M (February 2000). "A novel spontaneous missense mutation in VMD2 gene is a cause of a best macular dystrophy sporadic case".American Journal of Ophthalmology.129 (2):260–2.doi:10.1016/S0002-9394(99)00327-X.PMID10682987.
Lotery AJ, Munier FL, Fishman GA, Weleber RG, Jacobson SG, Affatigato LM, Nichols BE, Schorderet DF, Sheffield VC, Stone EM (May 2000). "Allelic variation in the VMD2 gene in best disease and age-related macular degeneration".Investigative Ophthalmology & Visual Science.41 (6):1291–6.PMID10798642.
Eksandh L, Bakall B, Bauer B, Wadelius C, Andréasson S (June 2001). "Best's vitelliform macular dystrophy caused by a new mutation (Val89Ala) in the VMD2 gene".Ophthalmic Genetics.22 (2):107–15.doi:10.1076/opge.22.2.107.2226.PMID11449320.S2CID7035792.
