Mutation analysis of BEST1 in Japanese patients with Best's vitelliform macular dystrophy

Purpose To describe the clinical and genetic features of Japanese patients with Best's vitelliform macular dystrophy (BVMD). Patients and methods This study examined 22 patients, including 16 probands from 16 families with BVMD. Comprehensive ophthalmic examinations were performed, including dilated funduscopy, full-field electroretinography (ERG) and electro-oculography (EOG). BEST1 mutation analysis was performed by Sanger sequencing. Results All 16 probands exhibited characteristic BVMD fundus appearances, abnormal EOG, and normal ERG responses with the exception of one diabetic retinopathy proband. Genetic analysis identified 12 BEST1 variants in 13 probands (81%). Of these, 10 variants (p.T2A, p.R25W, p.F80L, p.V81M, p.A195V, p.R218H, p.G222E, p.V242M, p.D304del and p.E306D) have been previously reported in BVMD, while two variants (p.S7N and p.P346H) were novel, putative disease-causing variants. Single BEST1 variants were found in 12 probands. The one proband with compound heterozygous variants (p.S7N and p.R218H) exhibited typical BVMD phenotypes (pseudohypopyon stage and vitelliruptive stage in the right and left eyes, respectively). Conclusions Twelve different variants, two of which (p.S7N and p.P346H) were novel, were identified in the 13 Japanese families with BVMD. Compound heterozygous variants were found in one proband exhibiting a typical BVMD phenotype. Our results suggest that BEST1 variants do play a large role in Japanese patients with BVMD.

[1]  I. Audo,et al.  Frequency and clinical pattern of vitelliform macular dystrophy caused by mutations of interphotoreceptor matrix IMPG1 and IMPG2 genes. , 2014, Ophthalmology.

[2]  Xavier Zanlonghi,et al.  Mutations in IMPG1 cause vitelliform macular dystrophies. , 2013, American journal of human genetics.

[3]  F. Riemslag,et al.  Autosomal recessive bestrophinopathy: differential diagnosis and treatment options. , 2013, Ophthalmology.

[4]  F. Torricelli,et al.  BEST1 sequence variants in Italian patients with vitelliform macular dystrophy , 2012, Molecular vision.

[5]  D. Sharon,et al.  Frequency, genotype, and clinical spectrum of best vitelliform macular dystrophy: data from a national center in Denmark. , 2012, American journal of ophthalmology.

[6]  D. Sharon,et al.  A homozygous frameshift mutation in BEST1 causes the classical form of Best disease in an autosomal recessive mode. , 2011, Investigative ophthalmology & visual science.

[7]  G. Aguirre,et al.  Molecular consequences of BEST1 gene mutations in canine multifocal retinopathy predict functional implications for human bestrophinopathies. , 2011, Investigative ophthalmology & visual science.

[8]  D. Sharon,et al.  Clinical evaluation of two consanguineous families with homozygous mutations in BEST1 , 2011, Molecular vision.

[9]  C. Hamel,et al.  Systematic screening of BEST1 and PRPH2 in juvenile and adult vitelliform macular dystrophies: a rationale for molecular analysis. , 2011, Ophthalmology.

[10]  D. Mackey,et al.  AUTOSOMAL RECESSIVE VITELLIFORM MACULAR DYSTROPHY IN A LARGE COHORT OF VITELLIFORM MACULAR DYSTROPHY PATIENTS , 2011, Retina.

[11]  E. Stone,et al.  Autosomal recessive best vitelliform macular dystrophy: report of a family and management of early-onset neovascular complications. , 2011, Archives of ophthalmology.

[12]  K. Bigot,et al.  Phenotypic variability in a French family with a novel mutation in the BEST1 gene causing multifocal best vitelliform macular dystrophy , 2011, Molecular vision.

[13]  Kang Zhang,et al.  A novel haplotype with the R345W mutation in the EFEMP1 gene associated with autosomal dominant drusen in a Japanese family. , 2010, Investigative ophthalmology & visual science.

[14]  S. Jacobson,et al.  Missense mutations in a retinal pigment epithelium protein, bestrophin-1, cause retinitis pigmentosa. , 2009, American journal of human genetics.

[15]  S. Yoshida,et al.  VMD2 mutational analysis in a Japanese family with Best macular dystrophy , 2009, Oman journal of ophthalmology.

[16]  B. J. Klevering,et al.  The spectrum of ocular phenotypes caused by mutations in the BEST1 gene , 2009, Progress in Retinal and Eye Research.

[17]  G. Holder,et al.  Biallelic mutation of BEST1 causes a distinct retinopathy in humans. , 2008, American journal of human genetics.

[18]  L. Atchaneeyasakul,et al.  Mutation Analysis of the VMD2 Gene in Thai Families with Best Macular Dystrophy , 2008, Ophthalmic genetics.

[19]  F. Torricelli,et al.  A novel mutation in the VMD2 gene in an Italian family with Best maculopathy. , 2007, Journal francais d'ophtalmologie.

[20]  V. Drouin‐Garraud,et al.  New VMD2 gene mutations identified in patients affected by Best vitelliform macular dystrophy , 2006, Journal of Medical Genetics.

[21]  N. Dahl,et al.  Variant Phenotype of Best Vitelliform Macular Dystrophy Associated with Compound Heterozygous Mutations in VMD2 , 2006, Ophthalmic genetics.

[22]  Y. Yanagi,et al.  Identification of a novel VMD2 mutation in Japanese patients with Best disease , 2002, Ophthalmic genetics.

[23]  D. Schorderet,et al.  Identification of novel VMD2 gene mutations in patients with best vitelliform macular dystrophy , 2001, Human mutation.

[24]  V. Sheffield,et al.  Allelic variation in the VMD2 gene in best disease and age-related macular degeneration. , 2000, Investigative ophthalmology & visual science.

[25]  B. Lorenz,et al.  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 , 2000, European Journal of Human Genetics.

[26]  V. Sheffield,et al.  Allelic Variation in the VMD 2 Gene in Best Disease and Age-Related Macular Degeneration , 2000 .

[27]  P. Sieving,et al.  Bestrophin gene mutations in patients with Best vitelliform macular dystrophy. , 1999, Genomics.

[28]  C. Wadelius,et al.  The mutation spectrum of the bestrophin protein – functional implications , 1999, Human Genetics.

[29]  H. Stöhr,et al.  Mutations in a novel gene, VMD2, encoding a protein of unknown properties cause juvenile-onset vitelliform macular dystrophy (Best's disease). , 1998, Human molecular genetics.

[30]  M. Metzker,et al.  Identification of the gene responsible for Best macular dystrophy , 1998, Nature Genetics.

[31]  R. Carr,et al.  Polymorphous presentations in vitelliform macular dystrophy: subretinal neovascularisation and central choroidal atrophy. , 1978, The British journal of ophthalmology.