Ocular Phenotype Analysis of a Family With Biallelic Mutations in the BEST1 Gene

Dror Sharon; Sermed Al-Hamdani; Karl Engelsberg; Liliana Mizrahi-Meissonnier; Alexey Obolensky; Eyal Banin; Birgit Sander; Hanne Jensen; Michael Larsen; Patrik Schatz

doi:10.1016/j.ajo.2013.12.010

Ocular Phenotype Analysis of a Family With Biallelic Mutations in the BEST1 Gene

Dror Sharon, Sermed Al-Hamdani, Karl Engelsberg, Liliana Mizrahi-Meissonnier, Alexey Obolensky, Eyal Banin, Birgit Sander, Hanne Jensen, Michael Larsen, Patrik Schatz

Institut for Klinisk Medicin

12 Citationer (Scopus)

Abstract

PURPOSE: To investigate the genetic cause and perform a comprehensive clinical analysis of a Danish family with autosomal recessive bestrophinopathy; to investigate whether Bestrophin may be expressed in normal human retina.

DESIGN: Retrospective clinical and molecular genetic analysis and immunohistochemical observational study.

METHODS: setting: National referral center. participants: A family with 5 individuals and biallelic BEST1 mutations, and enucleated eyes from 2 individuals with nonaffected retinas. observation procedures: Molecular genetic analysis included sequencing of BEST1 and co-segregation analysis. Clinical investigations included electro-oculography, full-field electroretinography, multifocal electroretinography, spectral-domain optical coherence tomography, and fundus autofluorescence imaging. Immunohistochemical analysis was performed. main outcome measures: BEST1 mutations, imaging findings, electroretinography amplitudes, and implicit times.

RESULTS: The index case was compound heterozygous for p.A195V and a novel 15 base pair deletion leading to p.Q238L. The index case at age 10 demonstrated multifocal vitelliform changes that were hyperautofluorescent, cystoid macular edema in the inner nuclear layer, no light rise in the electro-oculography, and a reduced central but preserved peripheral retinal function by multifocal electroretinography. Full-field electroretinography demonstrated a reduced rod response and inner retina dysfunction. Retinal structure was normal in all 3 family members who carried a sequence change in BEST1. Electro-oculography light peak was reduced in both the mother and sister (heterozygous for p.Q238L). Immunohistochemistry could not confirm the presence of Bestrophin in normal human retina.

CONCLUSIONS: Because of a relatively well preserved retinal function, autosomal recessive bestrophinopathy may be a suitable first candidate, among the BEST1-related ocular conditions, for gene replacement therapy.

Originalsprog	Engelsk
Tidsskrift	American Journal of Ophthalmology
Vol/bind	157
Udgave nummer	3
Sider (fra-til)	697-709.e2
Antal sider	13
ISSN	0002-9394
DOI	https://doi.org/10.1016/j.ajo.2013.12.010
Status	Udgivet - mar. 2014

Adgang til dokumentet

10.1016/j.ajo.2013.12.010

Citationsformater

@article{cd04e0cdf826466c93acc37b550ee95e,

title = "Ocular Phenotype Analysis of a Family With Biallelic Mutations in the BEST1 Gene",

abstract = "PURPOSE: To investigate the genetic cause and perform a comprehensive clinical analysis of a Danish family with autosomal recessive bestrophinopathy; to investigate whether Bestrophin may be expressed in normal human retina.DESIGN: Retrospective clinical and molecular genetic analysis and immunohistochemical observational study.METHODS: setting: National referral center. participants: A family with 5 individuals and biallelic BEST1 mutations, and enucleated eyes from 2 individuals with nonaffected retinas. observation procedures: Molecular genetic analysis included sequencing of BEST1 and co-segregation analysis. Clinical investigations included electro-oculography, full-field electroretinography, multifocal electroretinography, spectral-domain optical coherence tomography, and fundus autofluorescence imaging. Immunohistochemical analysis was performed. main outcome measures: BEST1 mutations, imaging findings, electroretinography amplitudes, and implicit times.RESULTS: The index case was compound heterozygous for p.A195V and a novel 15 base pair deletion leading to p.Q238L. The index case at age 10 demonstrated multifocal vitelliform changes that were hyperautofluorescent, cystoid macular edema in the inner nuclear layer, no light rise in the electro-oculography, and a reduced central but preserved peripheral retinal function by multifocal electroretinography. Full-field electroretinography demonstrated a reduced rod response and inner retina dysfunction. Retinal structure was normal in all 3 family members who carried a sequence change in BEST1. Electro-oculography light peak was reduced in both the mother and sister (heterozygous for p.Q238L). Immunohistochemistry could not confirm the presence of Bestrophin in normal human retina.CONCLUSIONS: Because of a relatively well preserved retinal function, autosomal recessive bestrophinopathy may be a suitable first candidate, among the BEST1-related ocular conditions, for gene replacement therapy.",

keywords = "Adult, Alleles, Child, Chloride Channels, Electrooculography, Electroretinography, Eye Diseases, Hereditary, Eye Proteins, Female, Fluorescein Angiography, Fluorescent Antibody Technique, Indirect, Humans, Male, Middle Aged, Molecular Biology, Mutation, Pedigree, Phenotype, Retina, Retinal Diseases, Retrospective Studies, Tomography, Optical Coherence, Young Adult",

author = "Dror Sharon and Sermed Al-Hamdani and Karl Engelsberg and Liliana Mizrahi-Meissonnier and Alexey Obolensky and Eyal Banin and Birgit Sander and Hanne Jensen and Michael Larsen and Patrik Schatz",

year = "2014",

month = mar,

doi = "10.1016/j.ajo.2013.12.010",

language = "English",

volume = "157",

pages = "697--709.e2",

journal = "American Journal of Ophthalmology",

issn = "0002-9394",

publisher = "Elsevier",

number = "3",

}

TY - JOUR

T1 - Ocular Phenotype Analysis of a Family With Biallelic Mutations in the BEST1 Gene

AU - Sharon, Dror

AU - Al-Hamdani, Sermed

AU - Engelsberg, Karl

AU - Mizrahi-Meissonnier, Liliana

AU - Obolensky, Alexey

AU - Banin, Eyal

AU - Sander, Birgit

AU - Jensen, Hanne

AU - Larsen, Michael

AU - Schatz, Patrik

PY - 2014/3

Y1 - 2014/3

N2 - PURPOSE: To investigate the genetic cause and perform a comprehensive clinical analysis of a Danish family with autosomal recessive bestrophinopathy; to investigate whether Bestrophin may be expressed in normal human retina.DESIGN: Retrospective clinical and molecular genetic analysis and immunohistochemical observational study.METHODS: setting: National referral center. participants: A family with 5 individuals and biallelic BEST1 mutations, and enucleated eyes from 2 individuals with nonaffected retinas. observation procedures: Molecular genetic analysis included sequencing of BEST1 and co-segregation analysis. Clinical investigations included electro-oculography, full-field electroretinography, multifocal electroretinography, spectral-domain optical coherence tomography, and fundus autofluorescence imaging. Immunohistochemical analysis was performed. main outcome measures: BEST1 mutations, imaging findings, electroretinography amplitudes, and implicit times.RESULTS: The index case was compound heterozygous for p.A195V and a novel 15 base pair deletion leading to p.Q238L. The index case at age 10 demonstrated multifocal vitelliform changes that were hyperautofluorescent, cystoid macular edema in the inner nuclear layer, no light rise in the electro-oculography, and a reduced central but preserved peripheral retinal function by multifocal electroretinography. Full-field electroretinography demonstrated a reduced rod response and inner retina dysfunction. Retinal structure was normal in all 3 family members who carried a sequence change in BEST1. Electro-oculography light peak was reduced in both the mother and sister (heterozygous for p.Q238L). Immunohistochemistry could not confirm the presence of Bestrophin in normal human retina.CONCLUSIONS: Because of a relatively well preserved retinal function, autosomal recessive bestrophinopathy may be a suitable first candidate, among the BEST1-related ocular conditions, for gene replacement therapy.

AB - PURPOSE: To investigate the genetic cause and perform a comprehensive clinical analysis of a Danish family with autosomal recessive bestrophinopathy; to investigate whether Bestrophin may be expressed in normal human retina.DESIGN: Retrospective clinical and molecular genetic analysis and immunohistochemical observational study.METHODS: setting: National referral center. participants: A family with 5 individuals and biallelic BEST1 mutations, and enucleated eyes from 2 individuals with nonaffected retinas. observation procedures: Molecular genetic analysis included sequencing of BEST1 and co-segregation analysis. Clinical investigations included electro-oculography, full-field electroretinography, multifocal electroretinography, spectral-domain optical coherence tomography, and fundus autofluorescence imaging. Immunohistochemical analysis was performed. main outcome measures: BEST1 mutations, imaging findings, electroretinography amplitudes, and implicit times.RESULTS: The index case was compound heterozygous for p.A195V and a novel 15 base pair deletion leading to p.Q238L. The index case at age 10 demonstrated multifocal vitelliform changes that were hyperautofluorescent, cystoid macular edema in the inner nuclear layer, no light rise in the electro-oculography, and a reduced central but preserved peripheral retinal function by multifocal electroretinography. Full-field electroretinography demonstrated a reduced rod response and inner retina dysfunction. Retinal structure was normal in all 3 family members who carried a sequence change in BEST1. Electro-oculography light peak was reduced in both the mother and sister (heterozygous for p.Q238L). Immunohistochemistry could not confirm the presence of Bestrophin in normal human retina.CONCLUSIONS: Because of a relatively well preserved retinal function, autosomal recessive bestrophinopathy may be a suitable first candidate, among the BEST1-related ocular conditions, for gene replacement therapy.

KW - Adult

KW - Alleles

KW - Child

KW - Chloride Channels

KW - Electrooculography

KW - Electroretinography

KW - Eye Diseases, Hereditary

KW - Eye Proteins

KW - Female

KW - Fluorescein Angiography

KW - Fluorescent Antibody Technique, Indirect

KW - Humans

KW - Male

KW - Middle Aged

KW - Molecular Biology

KW - Mutation

KW - Pedigree

KW - Phenotype

KW - Retina

KW - Retinal Diseases

KW - Retrospective Studies

KW - Tomography, Optical Coherence

KW - Young Adult

U2 - 10.1016/j.ajo.2013.12.010

DO - 10.1016/j.ajo.2013.12.010

M3 - Journal article

C2 - 24345323

SN - 0002-9394

VL - 157

SP - 697-709.e2

JO - American Journal of Ophthalmology

JF - American Journal of Ophthalmology

IS - 3

ER -

Ocular Phenotype Analysis of a Family With Biallelic Mutations in the BEST1 Gene

Abstract

Adgang til dokumentet

Fingeraftryk

Citationsformater