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Specific Alleles of CLN7/MFSD8, a Protein That Localizes to Photoreceptor Synaptic Terminals, Cause a Spectrum of Nonsyndromic Retinal Dystrophy
- Source :
- NIHR BioResource-Rare Diseases & Uk Inherited Retinal Disease Consortium 2017, ' Specific alleles of CLN7/MFSD8, a protein that localizes to photoreceptor synaptic terminals, cause a spectrum of nonsyndromic retinal dystrophy ', Investigative Ophthalmology and Visual Science, vol. 58, no. 7, pp. 2906-2914 . https://doi.org/10.1167/iovs.16-20608
- Publication Year :
- 2017
-
Abstract
- PURPOSE. Recessive mutations in CLN7/MFSD8 usually cause variant late-infantile onset neuronal ceroid lipofuscinosis (vLINCL), a poorly understood neurodegenerative condition, though mutations may also cause nonsyndromic maculopathy. A series of 12 patients with nonsyndromic retinopathy due to novel CLN7/MFSD8 mutation combinations were investigated in this study. METHODS. Affected patients and their family members were recruited in ophthalmic clinics at each center where they were examined by retinal imaging and detailed electrophysiology. Whole exome or genome next generation sequencing was performed on genomic DNA from at least one affected family member. Immunofluorescence confocal microscopy of murine retina cross-sections were used to localize the protein. RESULTS. Compound heterozygous alleles were identified in six cases, one of which was always p.Glu336Gln. Such combinations resulted in isolated macular disease. Six further cases were homozygous for the variant p.Met454Thr, identified as a founder mutation of South Asian origin. Those patients had widespread generalized retinal disease, characterized by electroretinography as a rod-cone dystrophy with severe macular involvement. In addition, the photopic single flash electroretinograms demonstrated a reduced b- to a-wave amplitude ratio, suggesting dysfunction occurring after phototransduction. Immunohistology identified MFSD8 in the outer plexiform layer of the retina, a site rich in photoreceptor synapses. CONCLUSIONS. This study highlights a hierarchy of MFSD8 variant severity, predicting three consequences of mutation: (1) nonsyndromic localized maculopathy, (2) nonsyndromic widespread retinopathy, or (3) syndromic neurological disease. The data also shed light on the underlying pathogenesis by implicating the photoreceptor synaptic terminals as the major site of retinal disease.
- Subjects :
- Adult
Male
genetic structures
Retinal dystrophy
education
DNA Mutational Analysis
Presynaptic Terminals
Biology
Photoreceptor synapse
Immunohistology
03 medical and health sciences
0302 clinical medicine
Dna genetics
Retinitis pigmentosa
Retinal Dystrophies
Electroretinography
medicine
Humans
Exome
DNA sequencing
Microscopy, Confocal
Blindness
Macular degeneration
Homozygote
A protein
High-Throughput Nucleotide Sequencing
Membrane Transport Proteins
Anatomy
DNA
Middle Aged
medicine.disease
eye diseases
Pedigree
Multicenter study
Research centre
Mutation
030221 ophthalmology & optometry
Optometry
Female
sense organs
030217 neurology & neurosurgery
Photoreceptor Cells, Vertebrate
Subjects
Details
- ISSN :
- 15525783
- Volume :
- 58
- Issue :
- 7
- Database :
- OpenAIRE
- Journal :
- Investigative ophthalmologyvisual science
- Accession number :
- edsair.doi.dedup.....5382a00694ac593e06734193e1f119a5