Specific Alleles of CLN7/MFSD8, a Protein That Localizes to Photoreceptor Synaptic Terminals, Cause a Spectrum of Nonsyndromic Retinal Dystrophy
AuthorKhan, Kamron N.
El-Asrag, Mohammed E.
Ku, Cristy A.
Holder, Graham E.
Poulter, James A.
Scholl, Hendrik P.
Raymond, F. Lucy
Inglehearn, Chris F.
Pennesi, Mark E.
Moore, Anthony T.
Webster, Andrew R.
AffiliationUniv Arizona, Coll Med
MetadataShow full item record
PublisherASSOC RESEARCH VISION OPHTHALMOLOGY INC
CitationSpecific Alleles of CLN7/MFSD8, a Protein That Localizes to Photoreceptor Synaptic Terminals, Cause a Spectrum of Nonsyndromic Retinal Dystroph 2017, 58 (7):2906 Investigative Opthalmology & Visual Science
RightsCopyright © 2017 The Authors. This work is licensed under a Creative Commons Attribution 4.0 International License.
Collection InformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at firstname.lastname@example.org.
AbstractPURPOSE. 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.
NoteOpen Access Journal.
VersionFinal published version
SponsorsNERC (Yorkshire branch); National Institute for Health Research England (NIHR) for the NIHR BioResource-Rare Diseases project [RG65966]; Biomedical Research Centre at Moorfields Eye Hospital; University College London Institute of Ophthalmology; Moorfields Eye Hospital Special Trustees; Foundation Fighting Blindness-USA; Research to Prevent Blindness-Casey Eye Institute; RP Fighting Blindness; FFB Career Development Award; FFB Enhanced Career Development Award; NIHR Rare Disease Fellowship; Fight For Sight (RP Genome Project) [GR586]
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