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

Abstract

Biallelic MFSD8 variants are an established cause of severe late‐infantile subtype of neuronal ceroid lipofuscinosis (v‐LINCL), a severe lysosomal storage disorder, but have also been associated with nonsyndromic adult‐onset maculopathy. Here, we functionally characterized two novel MFSD8 variants found in a child with juvenile isolated maculopathy, in order to establish a refined prognosis. ABCA4 locus resequencing was followed by the analysis of other inherited retinal disease genes by whole exome sequencing (WES). Minigene assays and cDNA sequencing were used to assess the effect of a novel MFSD8 splice variant. MFSD8 expression was quantified with qPCR and overexpression studies were analyzed by immunoblotting. Transmission electron microscopy (TEM) was performed on a skin biopsy and ophthalmological and neurological re‐examinations were conducted. WES revealed two novel MFSD8 variants: c.[590del];[439+3A>C] p.[Gly197Valfs*2];[Ile67Glufs*3]. Characterization of the c.439+3A>C variant via splice assays showed exon‐skipping (p.Ile67Glufs*3), while overexpression studies of the corresponding protein indicated expression of a truncated polypeptide. In addition, a significantly reduced MFSD8 RNA expression was noted in patient's lymphocytes. TEM of a skin biopsy revealed typical v‐LINCL lipopigment inclusions while neurological imaging of the proband displayed subtle cerebellar atrophy. Functional characterization demonstrated the pathogenicity of two novel MFSD8 variants, found in a child with an initial diagnosis of juvenile isolated maculopathy but likely evolving to v‐LINCL with a protracted disease course. Our study allowed a refined neurological prognosis in the proband and expands the natural history of MFSD8‐associated disease.

Usher syndrome type IV: clinically and molecularly confirmed by novel ARSG variants

“…Remarkably, a similar situation has been described for other genes causative for lysosomal storage diseases. While variants in genes associated with neuronal ceroid lipofuscinosis ( CLN3 (OMIM 607042), CLN5 (OMIM 608102), and MFSD8 / CLN7 (OMIM611124)) typically lead to severe neuronal dysfunction and lysosomal storage in neurons and the peripheral tissues, some variants present with isolated retina disease (Bauwens et al 2020 ; Khan et al 2017 ; Ku et al 2017 ; Magliyah et al 2021 ). Similarly, variants in HGSNAT (OMIM 610453) are associated with mucopolysaccharidosis in the vast majority of patients, but isolated retina degeneration has also been described (Haer-Wigman et al 2015 ).…”

CLN7 mutation causes aberrant redistribution of protein isoforms and contributes to Batten disease pathobiology

“…There is emerging evidence for gain-of-function caused by CLN7 mutation in other neurodegenerative spectrum diseases where CLN7/MFSD8 mutation has been shown to contribute to ALS/FTD (20,36). Some allelic mutations in CLN7 can contribute to retinopathies including retinitis pigmentosa and macular dystrophy (37)(38)(39). CLN7 has been shown to co-localize with post-synaptic density marker 95 (PSD-95) in the mouse retina indicating that it may play more complex roles in specialist neural cell-types (39).…”

Neuronal Ceroid Lipofuscinosis: The Multifaceted Approach to the Clinical Issues, an Overview

“…Whether maculopathy precedes cognitive impairment in CLN3 disease, or if both visual impairment and mild cognitive failure occur at around the same time ( 98 ) is still the subject of discussion. Biallelic variants of the MFSD8 gene may be associated with isolated juvenile maculopathy, evolving into a slowly progressive encephalopathy with protracted course ( 99 ). Conversely, late visual impairment, or even long lasting preservation of visual function can occur in CLN5 and CLN6 diseases ( 92 , 100 ).…”