当前位置： SCI文献检索 > OPHTHALMOLOGY期刊下所有文献 > Mutations in MFSD8, encoding a lysosomal membrane protein, are associated with nonsyndromic autosomal recessive macular dystrophy.

Mutations in MFSD8, encoding a lysosomal membrane protein, are associated with nonsyndromic autosomal recessive macular dystrophy.

Abstract：

PURPOSE:This study aimed to identify the genetic defects in 2 families with autosomal recessive macular dystrophy with central cone involvement. DESIGN:Case series. PARTICIPANTS:Two families and a cohort of 244 individuals with various inherited maculopathies and cone disorders. METHODS:Genome-wide linkage analysis and exome sequencing were performed in 1 large family with 5 affected individuals. In addition, exome sequencing was performed in the proband of a second family. Subsequent analysis of the identified mutations in 244 patients was performed by Sanger sequencing or restriction enzyme digestion. The medical history of individuals carrying the MFSD8 variants was reviewed and additional ophthalmic examinations were performed, including electroretinography (ERG), multifocal ERG (mfERG), perimetry, optical coherence tomography (OCT), fundus autofluorescence, and fundus photography. MAIN OUTCOME MEASURES:MFSD8 variants, age at diagnosis, visual acuity, fundus appearance, color vision defects, visual field, ERG, mfERG, fundus autofluorescence, and OCT findings. RESULTS:Compound heterozygous variants in MFSD8, a gene encoding a lysosomal transmembrane protein, were identified in 2 families with macular dystrophy with a normal or subnormal ERG, but reduced mfERG. In both families, a heterozygous missense variant p.Glu336Gln was identified, which was predicted to have a mild effect on the protein. In the first family, a protein-truncating variant (p.Glu381*) was identified on the other allele, and in the second family, a variant (c.1102G>C) was identified that results in a splicing defect leading to skipping of exon 11 (p.Lys333Lysfs*3). The p.Glu336Gln allele was found to be significantly enriched in patients with maculopathies and cone disorders (6/488) compared with ethnically matched controls (35/18 682; P < 0.0001), suggesting that it may act as a genetic modifier. CONCLUSIONS:In this study, we identified variants in MFSD8 as a novel cause of nonsyndromic autosomal recessive macular dystrophy with central cone involvement. Affected individuals showed no neurologic features typical for variant late-infantile neuronal ceroid lipofuscinosis (vLINCL), a severe and devastating multisystem lysosomal storage disease previously associated with mutations in MFSD8. We propose a genotype-phenotype model in which a combination of a severe and a mild variant cause nonsyndromic macular dystrophy with central cone involvement, and 2 severe mutations cause vLINCL.

journal_name

Ophthalmology

journal_title

Ophthalmology

authors

Roosing S,van den Born LI,Sangermano R,Banfi S,Koenekoop RK,Zonneveld-Vrieling MN,Klaver CC,van Lith-Verhoeven JJ,Cremers FP,den Hollander AI,Hoyng CB

doi

10.1016/j.ophtha.2014.07.040

subject

Has Abstract

pub_date

2015-01-01 00:00:00

pages

170-9

issue

eissn

0161-6420

issn

1549-4713

pii

S0161-6420(14)00684-8

journal_volume

122

pub_type

杂志文章

在线工具

Mutations in MFSD8, encoding a lysosomal membrane protein, are associated with nonsyndromic autosomal recessive macular dystrophy.