Top

Published in:

Open Access 01-06-2016 | Clinical Case Report

Detailed analysis of family with autosomal recessive bestrophinopathy associated with new BEST1 mutation

Authors: Daiki Kubota, Kiyoko Gocho, Keiichiro Akeo, Sachiko Kikuchi, Michitaka Sugahara, Celso Soiti Matsumoto, Kei Shinoda, Atsushi Mizota, Kunihiko Yamaki, Hiroshi Takahashi, Shuhei Kameya

Published in: Documenta Ophthalmologica | Issue 3/2016

Abstract

Purpose

To describe the clinical and genetic findings in a patient with autosomal recessive bestrophinopathy (ARB) and his healthy parents.

Methods

The patient and his healthy non-consanguineous parents underwent detailed ophthalmic evaluations including electro-oculography (EOG), spectral-domain optical coherence tomography (SD-OCT), and fundus autofluorescence (FAF) imaging. Mutation analysis of the BEST1 gene was performed by Sanger sequencing.

Results

The FAF images showed multiple spots of increased autofluorescence, and the sites of these spots corresponded to the yellowish deposits detected by ophthalmoscopy. SD-OCT showed cystoid macular changes and a shallow serous macular detachment. The Arden ratio of the EOG was markedly reduced to 1.1 in both eyes. Genetic analysis of the proband detected two sequence variants of the BEST1 gene in the heterozygous state: a novel variant c.717delG, p.V239VfsX2 and an already described c.763C>T, p.R255W variant associated with Best vitelliform macular dystrophy and ARB. The proband’s father carried the c.717delG, p.V239VfsX2 variant in the heterozygous state, and the mother carried the c.763C>T, p.R255W variant in the heterozygous state. The parents who were heterozygous for the BEST1 variants had normal visual acuity, EOG, SD-OCT, and FAF images.

Conclusions

In a truncating BEST1 mutation, the phenotype associated with ARB is most likely due to a marked decrease in the expression of BEST1 promoted by the nonsense-mediated decay surveillance mechanism, and it may depend on the position of the premature termination of the codon created.

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 (1998) Identification of the gene responsible for Best macular dystrophy. Nat Genet 19:241–247CrossRefPubMed

Marmorstein AD, Marmorstein LY, Rayborn M, Wang X, Hollyfield JG, Petrukhin K (2000) 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 USA 97:12758–12763CrossRefPubMedPubMedCentral

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 USA 99:4008–4013CrossRefPubMedPubMedCentral

Rosenthal R, Bakall B, Kinnick T, Peachey N, Wimmers S, Wadelius C, Marmorstein A, Strauss O (2006) Expression of bestrophin-1, the product of the VMD2 gene, modulates voltage-dependent Ca²⁺ channels in retinal pigment epithelial cells. FASEB J 20:178–180PubMed

Qu Z, Hartzell HC (2008) Bestrophin Cl-channels are highly permeable to HCO3. Am J Physiol Cell Physiol 294:C1371–C1377CrossRefPubMedPubMedCentral

Boon CJ, Klevering BJ, Leroy BP, Hoyng CB, Keunen JE, den Hollander AI (2009) The spectrum of ocular phenotypes caused by mutations in the BEST1 gene. Prog Retin Eye Res 28:187–205CrossRefPubMed

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 (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 8:286–292CrossRefPubMed

Yardley J, Leroy BP, Hart-Holden N, Lafaut BA, Loeys B, Messiaen LM, Perveen R, Reddy MA, Bhattacharya SS, Traboulsi E, Baralle D, De Laey JJ, Puech B, Kestelyn P, Moore AT, Manson FD, Black GC (2004) Mutations of VMD2 splicing regulators cause nanophthalmos and autosomal dominant vitreo-retinochoroidopathy (ADVIRC). Invest Ophthalmol Vis Sci 45:3683–3689CrossRefPubMed

Davidson AE, Millar ID, Urquhart JE, Burgess-Mullan R, Shweikh Y, Parry N, O’Sullivan J, Maher GJ, McKibbin M, Downes SM, Lotery AJ, Jacobson SG, Brown PD, Black GC, Manson FD (2009) Missense mutations in a retinal pigment epithelium protein, bestrophin-1, cause retinitis pigmentosa. Am J Hum Genet 85:581–592CrossRefPubMedPubMedCentral

10.

Michaelides M, Urquhart J, Holder GE, Restori M, Kayali N, Manson FD, Black GC (2006) Evidence of genetic heterogeneity in MRCS (microcornea, rod-cone dystrophy, cataract, and posterior staphyloma) syndrome. Am J Ophthalmol 141:418–420CrossRefPubMed

11.

Burgess R, Millar ID, Leroy BP, Urquhart JE, Fearon IM, De Baere E, Brown PD, Robson AG, Wright GA, Kestelyn P, Holder GE, Webster AR, Manson FD, Black GC (2008) Biallelic mutation of BEST1 causes a distinct retinopathy in humans. Am J Hum Genet 82:19–31CrossRefPubMedPubMedCentral

12.

Toto L, Boon CJ, Di Antonio L, Battaglia Parodi M, Mastropasqua R, Antonucci I, Stuppia L, Mastropasqua L (2015) BESTROPHINOPATHY: a spectrum of ocular abnormalities caused by the c.614T>C mutation in the BEST1 gene. Retina. doi:10.1097/IAE.0000000000000950

13.

Krämer F, Mohr N, Kellner U, Rudolph G, Weber BH (2003) Ten novel mutations in VMD2 associated with Best macular dystrophy (BMD). Hum Mutat 22:418CrossRefPubMed

14.

Lotery AJ, Munier FL, Fishman GA, Weleber RG, Jacobson SG, Affatigato LM, Nichols BE, Schorderet DF, Sheffield VC, Stone EM (2000) Allelic variation in the VMD2 gene in best disease and age-related macular degeneration. Invest Ophthalmol Vis Sci 41:1291–1296PubMed

15.

Boon CJ, Klevering BJ, den Hollander AI, Zonneveld MN, Theelen T, Cremers FP, Hoyng CB (2007) Clinical and genetic heterogeneity in multifocal vitelliform dystrophy. Arch Ophthalmol 125:1100–1106CrossRefPubMed

16.

Bitner H, Mizrahi-Meissonnier L, Griefner G, Erdinest I, Sharon D, Banin E (2011) A homozygous frameshift mutation in BEST1 causes the classical form of Best disease in an autosomal recessive mode. Invest Ophthalmol Vis Sci 52:5332–5338CrossRefPubMed

17.

Burgess R, MacLaren RE, Davidson AE, Urquhart JE, Holder GE, Robson AG, Moore AT, Keefe RO, Black GC, Manson FD (2009) ADVIRC is caused by distinct mutations in BEST1 that alter pre-mRNA splicing. J Med Genet 46:620–625CrossRefPubMed

18.

Davidson AE, Sergouniotis PI, Burgess-Mullan R, Hart-Holden N, Low S, Foster PJ, Manson FD, Black GC, Webster AR (2010) A synonymous codon variant in two patients with autosomal recessive bestrophinopathy alters in vitro splicing of BEST1. Mol Vis 16:2916–2922PubMedPubMedCentral

19.

Guerriero S, Preising MN, Ciccolella N, Causio F, Lorenz B, Fischetto R (2011) Autosomal recessive bestrophinopathy: new observations on the retinal phenotype—clinical and molecular report of an Italian family. Ophthalmologica 225:228–235CrossRefPubMed

20.

Piñeiro-Gallego T, Álvarez M, Pereiro I, Campos S, Sharon D, Schatz P, Valverde D (2011) Clinical evaluation of two consanguineous families with homozygous mutations in BEST1. Mol Vis 17:1607–1617PubMedPubMedCentral

21.

Borman AD, Davidson AE, O’Sullivan J, Thompson DA, Robson AG, De Baere E, Black GC, Webster AR, Holder GE, Leroy BP, Manson FD, Moore AT (2011) Childhood-onset autosomal recessive bestrophinopathy. Arch Ophthalmol 129:1088–1093CrossRefPubMed

22.

Boon CJ, van den Born LI, Visser L, Keunen JE, Bergen AA, Booij JC, Riemslag FC, Florijn RJ, van Schooneveld MJ (2013) Autosomal recessive bestrophinopathy: differential diagnosis and treatment options. Ophthalmology 120:809–820CrossRefPubMed

23.

Sharon D, Al-Hamdani S, Engelsberg K, Mizrahi-Meissonnier L, Obolensky A, Banin E, Sander B, Jensen H, Larsen M, Schatz P (2014) Ocular phenotype analysis of a family with biallelic mutations in the BEST1 gene. Am J Ophthalmol 157:697–709CrossRefPubMed

24.

Fung AT, Yzer S, Goldberg N, Wang H, Nissen M, Giovannini A, Merriam JE, Bukanova EN, Cai C, Yannuzzi LA, Tsang SH, Allikmets R (2015) New best1 mutations in autosomal recessive bestrophinopathy. Retina 35:773–782CrossRefPubMedPubMedCentral

25.

Gerth C, Zawadzki RJ, Werner JS, Héon E (2009) Detailed analysis of retinal function and morphology in a patient with autosomal recessive bestrophinopathy (ARB). Doc Ophthalmol 118:239–246CrossRefPubMedPubMedCentral

26.

Pomares E, Burés-Jelstrup A, Ruiz-Nogales S, Corcóstegui B, González-Duarte R, Navarro R (2012) Nonsense-mediated decay as the molecular cause for autosomal recessive bestrophinopathy in two unrelated families. Invest Ophthalmol Vis Sci 53:532–537CrossRefPubMed

27.

Schatz P, Klar J, Andréasson S, Ponjavic V, Dahl N (2006) Variant phenotype of Best vitelliform macular dystrophy associated with compound heterozygous mutations in VMD2. Ophthalmic Genet 27:51–56CrossRefPubMed

28.

Wong RL, Hou P, Choy KW, Chiang SW, Tam PO, Li H, Chan WM, Lam DS, Pang CP, Lai TY (2010) Novel and homozygous BEST1 mutations in Chinese patients with Best vitelliform macular dystrophy. Retina 30:820–827CrossRefPubMed

29.

Tian R, Yang G, Wang J, Chen Y (2014) BEST1 gene mutations in Chinese patients with bestrophinopathy. Mol Vis 20:1594–1604PubMedPubMedCentral

30.

Lacassagne E, Dhuez A, Rigaudière F, Dansault A, Vêtu C, Bigot K, Vieira V, Puech B, Defoort-Dhellemmes S, Abitbol M (2011) Phenotypic variability in a French family with a novel mutation in the BEST1 gene causing multifocal best vitelliform macular dystrophy. Mol Vis 17:309–322PubMedPubMedCentral

31.

Silva RA, Berrocal AM, Lam BL, Albini TA (2013) Novel mutation in BEST1 associated with retinoschisis. JAMA Ophthalmol 131:794–798. Erratum in (2013): JAMA Ophthalmol 131:1249

32.

Kinnick TR, Mullins RF, Dev S, Leys M, Mackey DA, Kay CN, Lam BL, Fishman GA, Traboulsi E, Iezzi R, Stone EM (2011) Autosomal recessive vitelliform macular dystrophy in a large cohort of vitelliform macular dystrophy patients. Retina 31:581–595CrossRefPubMed

33.

Sodi A, Menchini F, Manitto MP, Passerini I, Murro V, Torricelli F, Menchini U (2011) Ocular phenotypes associated with biallelic mutations in BEST1 in Italian patients. Mol Vis 17:3078–3087PubMedPubMedCentral

Title: Detailed analysis of family with autosomal recessive bestrophinopathy associated with new BEST1 mutation
Authors: Daiki Kubota
Kiyoko Gocho
Keiichiro Akeo
Sachiko Kikuchi
Michitaka Sugahara
Celso Soiti Matsumoto
Kei Shinoda
Atsushi Mizota
Kunihiko Yamaki
Hiroshi Takahashi
Shuhei Kameya
Publication date: 01-06-2016
Publisher: Springer Berlin Heidelberg
Published in: Documenta Ophthalmologica / Issue 3/2016
Print ISSN: 0012-4486
Electronic ISSN: 1573-2622
DOI: https://doi.org/10.1007/s10633-016-9540-3

At a glance: The STEP trials

Springer Medicine

Detailed analysis of family with autosomal recessive bestrophinopathy associated with new BEST1 mutation

Abstract

Purpose

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 3/2016

Two-color pupillometry in enhanced S-cone syndrome caused by NR2E3 mutations

The diagnosis and assessment of visual function in Singaporean children with electrophysiology: 10-year results

Comparison of photopic negative response (PhNR) between focal macular and full-field electroretinograms in monkeys

Witnessing the first sign of retinitis pigmentosa onset in the allegedly normal eye of a case of unilateral RP: a 30-year follow-up

Erratum to: Witnessing the first sign of retinitis pigmentosa onset in the allegedly normal eye of a case of unilateral RP: a 30-year follow-up

Age-related change in fast adaptation mechanisms measured with the scotopic full-field ERG