Specific Alleles of CLN7/MFSD8, a Protein That Localizes to Photoreceptor Synaptic Terminals, Cause a Spectrum of Nonsyndromic Retinal Dystrophy

Abstract

Citation: Khan KN, El-Asrag ME, Ku CA, et al.; for NIHR BioResource-Rare Diseases and UK Inherited Retinal Disease Consortium. Specific alleles of CLN7/ MFSD8, a protein that localizes to photoreceptor synaptic terminals, cause a spectrum of nonsyndromic retinal dystrophy. Invest Ophthalmol Vis Sci. 2017;58:290658: -291458: . DOI:10.1167 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.

Functional characterization of novel MFSD8 pathogenic variants anticipates neurological involvement in juvenile isolated maculopathy

“…Recently, Khan et al discussed a synaptic origin of the MFSD8‐ associated retinal disease based on the observation that ERG abnormalities seen in the MFSD8‐ patients reported are indicative of a post‐phototransduction abnormality and that murine MFSD8 localizes to the photoreceptor presynaptic terminals in the outer plexiform layer . The ocular phenotype in the patients studied suggests that, of all affected cell types, macular photoreceptors would be most sensitive to MFSD8 mutations, followed by the extramacular photoreceptors, with cortical neurons being the most resistant.…”

“…At this moment, it is unclear why certain MFSD8 missense variants act as functional null alleles and give rise to the syndromic early‐onset v‐LINCL in a similar fashion as do frameshift variants, while other missense variants, such as p.Glu336Gln, p.Met454Thr, and p.Arg482Pro are able to lead to an isolated maculopathy or retinopathy . A recent report on known biallelic MFSD8 variants previously described in v‐LINCL but occurring in patients with an isolated maculopathy in this study raises even more questions and points to possible cis ‐ or trans ‐acting modifiers .…”

“…Isolated macular dystrophies are characterized by degeneration of the central inner retina. Up to now, isolated maculopathies were found to be associated with over 26 genes and 2 loci, of which ATP binding cassette subfamily A member 4 gene ( ABCA4 ) is the most frequently involved and the Major Facilitator Superfamily Domain containing Protein‐8 gene ( MFSD8 , encoding CLN7) one of the more recently identified genes . The associated phenotype of the latter is characterized by macular dystrophy with central cone involvement or widespread retinopathy.…”

“…The associated phenotype of the latter is characterized by macular dystrophy with central cone involvement or widespread retinopathy. This has been attributed to the combination of hypomorphic and loss‐of‐function MFSD8 alleles or biallelic mild MFSD8 alleles . Biallelic loss‐of‐function MFSD8 variants on other hand, display a subtype of neuronal ceroid lipofuscinosis (NCL), named variant late‐infantile NCL (v‐LINCL, CLN7, NCL7), which is a severe lysosomal storage disorder leading to neurodegeneration .…”

“…Protein-8 gene (MFSD8, encoding CLN7) one of the more recently identified genes. [1][2][3][4] The associated phenotype of the latter is characterized by macular dystrophy with central cone involvement or widespread retinopathy. This has been attributed to the combination of hypomorphic and loss-of-function MFSD8 alleles or biallelic mild MFSD8 alleles.…”