Title |
Specific Alleles of CLN7/MFSD8, a Protein That Localizes to Photoreceptor Synaptic Terminals, Cause a Spectrum of Nonsyndromic Retinal DystrophyMFSD8 Mutations Cause Synaptic Disease
|
---|---|
Published in |
Investigative Ophthalmology & Visual Science, June 2017
|
DOI | 10.1167/iovs.16-20608 |
Pubmed ID | |
Authors |
Kamron N. Khan, Mohammed E. El-Asrag, Cristy A. Ku, Graham E. Holder, Martin McKibbin, Gavin Arno, James A. Poulter, Keren Carss, Tejaswi Bommireddy, Saghar Bagheri, Benjamin Bakall, Hendrik P. Scholl, F. Lucy Raymond, Carmel Toomes, Chris F. Inglehearn, Mark E. Pennesi, Anthony T. Moore, Michel Michaelides, Andrew R. Webster, Manir Ali |
Abstract |
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. 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. 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. 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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 2 | 50% |
Unknown | 2 | 50% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 3 | 75% |
Scientists | 1 | 25% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 50 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 10 | 20% |
Student > Ph. D. Student | 6 | 12% |
Student > Doctoral Student | 5 | 10% |
Student > Master | 4 | 8% |
Student > Postgraduate | 3 | 6% |
Other | 10 | 20% |
Unknown | 12 | 24% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 13 | 26% |
Medicine and Dentistry | 11 | 22% |
Agricultural and Biological Sciences | 5 | 10% |
Nursing and Health Professions | 2 | 4% |
Immunology and Microbiology | 2 | 4% |
Other | 4 | 8% |
Unknown | 13 | 26% |