The Novel Neuronal Ceroid Lipofuscinosis Gene MFSD8 Encodes a Putative Lysosomal Transporter

Abstract

The late-infantile-onset forms are the most genetically heterogeneous group among the autosomal recessively inherited neurodegenerative disorders, the neuronal ceroid lipofuscinoses (NCLs). The Turkish variant was initially considered to be a distinct genetic entity, with clinical presentation similar to that of other forms of late-infantile-onset NCL (LINCL), including age at onset from 2 to 7 years, epileptic seizures, psychomotor deterioration, myoclonus, loss of vision, and premature death. However, Turkish variant LINCL was recently found to be genetically heterogeneous, because mutations in two genes, CLN6 and CLN8, were identified to underlie the disease phenotype in a subset of patients. After a genomewide scan with single-nucleotide-polymorphism markers and homozygosity mapping in nine Turkish families and one Indian family, not linked to any of the known NCL loci, we mapped a novel variant LINCL locus to chromosome 4q28.1-q28.2 in five families. We identified six different mutations in the MFSD8 gene (previously denoted "MGC33302"), which encodes a novel polytopic 518-amino acid membrane protein that belongs to the major facilitator superfamily of transporter proteins. MFSD8 is expressed ubiquitously, with several alternatively spliced variants. Like the majority of the previously identified NCL proteins, MFSD8 localizes mainly to the lysosomal compartment. However, the function of MFSD8 remains to be elucidated. Analysis of the genome-scan data suggests the existence of at least three more genes in the remaining five families, further corroborating the great genetic heterogeneity of LINCLs.

Mutations in MFSD8/CLN7 are a frequent cause of variant-late infantile neuronal ceroid lipofuscinosis

“…All this fits well with a clinical diagnosis of NCL. Generalized slowing at EEG in many children, with photic responses in one case, were recorded, resembling what is found in classical late-infantile NCL with mutations in CLN2 (Haltia, 2006).A total of 11 different sequence changes were detected in the coding regions or consensus splice sites; 10 of these are novel mutations whereas one has been previously reported (Siintola et al, 2007). We also identified two new heterozygous variants (c.334C>T/p.Leu112Leu; c.1089A>G/p.Lys363Lys) which were present in 3% and 5% of control alleles respectively.…”

“…The CLN7 form was first described in variant-late infantile NCL (v-LINCL) children from Turkey (Mitchell et al, 2001;Topçu et al, 2004), and six different mutations were identified in a new gene, MFSD8/CLN7 (MIM# 611124; Siintola et al, 2007), in five Turkish and one Indian kindred. Recently, a new c.362A>G variant has been reported in an Egyptian family (Stogmann et al, 2008).…”

“…Only first-degree relatives in five families (cases #2, 3, and 6-8) could be genotyped a posteriori in peripheral blood DNA with fluorescently-labeled microsatellite markers surrounding the CLN7 locus as reported (Siintola et al, 2007). Haplotypes were constructed manually assuming a minimal number of recombination.…”

Phenotypic characterization of a mouse model of juvenile neuronal ceroid lipofuscinosis

“…Currently there are no known treatments to delay or halt the progression of the NCLs; the development of therapeutic interventions has been impeded by the lack of defined objective markers of disease status. In humans, the different forms of NCL result from mutations in at least eight distinct genes (Goebel and Wisniewski, 2004;Siintola et al, 2006;Siintola et al, 2007;Steinfeld et al, 2006;). …”

Neuronal ceroid-lipofuscinoses

“…CLN6 (LINCL, Costa Rican/Turkish/Indian/Roma Gypsy/Portugal variants) is caused by mutations in CLN6 [29][30][31]. CLN7 (INCL, Turkish/Indian variants) has been associated with a novel gene, MFSD8, which encodes a membrane protein belonging to the major facilitator superfamily of transporter proteins [32]. CLN8, which includes Northern epilepsy or progressive epilepsy with mental retardation (EPMR) and LINCL, Turkish variant, is caused by mutations in CLN8 [33][34][35].…”