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

Susanne Roosing, L Ingeborgh van den Born, Riccardo Sangermano, Sandro Banfi, Robert K Koenekoop, Marijke N Zonneveld-Vrieling, Caroline C W Klaver, Janneke J C van Lith-Verhoeven, Frans P M Cremers, Anneke I den Hollander, Carel B Hoyng

Research output: Contribution to journalArticleResearchpeer-review


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.

Original languageEnglish
Pages (from-to)170-9
Number of pages10
Issue number1
Publication statusPublished - Jan 2015


  • Adult
  • Aged
  • DNA Mutational Analysis
  • Electroretinography
  • Exome/genetics
  • Female
  • Genome-Wide Association Study
  • Humans
  • Lysosome-Associated Membrane Glycoproteins/genetics
  • Macular Degeneration/genetics
  • Male
  • Membrane Transport Proteins/genetics
  • Middle Aged
  • Mutation
  • Pedigree
  • Tomography, Optical Coherence
  • Visual Field Tests


Dive into the research topics of 'Mutations in MFSD8, encoding a lysosomal membrane protein, are associated with nonsyndromic autosomal recessive macular dystrophy'. Together they form a unique fingerprint.

Cite this