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

Folkhälsan Institute of Genetics, Department of Medical Genetics and Neuroscience Center, University of Helsinki, Finland.
Brain (Impact Factor: 9.2). 02/2009; 132(Pt 3):810-9. DOI: 10.1093/brain/awn366
Source: PubMed

ABSTRACT The neuronal ceroid lipofuscinoses (NCLs), the most common neurodegenerative disorders of childhood, are characterized by the accumulation of autofluorescent storage material mainly in neurons. Although clinically rather uniform, variant late-infantile onset NCL (vLINCL) is genetically heterogeneous with four major underlying genes identified so far. We evaluated the genetic background underlying vLINCL in 119 patients, and specifically analysed the recently reported CLN7/MFSD8 gene for mutations in 80 patients. Clinical data were collected from the CLN7/MFSD8 mutation positive patients. Eight novel CLN7/MFSD8 mutations and seven novel mutations in the CLN1/PPT1, CLN2/TPP1, CLN5, CLN6 and CLN8 genes were identified in patients of various ethnic origins. A significant group of Roma patients originating from the former Czechoslovakia was shown to bear the c.881C>A (p.Thr294Lys) mutation in CLN7/MFSD8, possibly due to a founder effect. With one exception, the CLN7/MFSD8 mutation positive patients present a phenotype indistinguishable from the other vLINCL forms. In one patient with an in-frame amino acid substitution mutation in CLN7/MFSD8, the disease onset was later and the disease course less aggressive than in variant late-infantile NCL. Our findings raise the total number of CLN7/MFSD8 mutations to 14 with the majority of families having private mutations. Our study confirms that CLN7/MFSD8 defects are not restricted to the Turkish population, as initially anticipated, but are a relatively common cause of NCL in different populations. CLN7/MFSD8 should be considered a diagnostic alternative not only in variant late-infantile but also later onset NCL forms with a more protracted disease course. A significant number of NCL patients in Turkey exist, in which the underlying genetic defect remains to be determined.

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    • "FP, n = 2 E3, p.Arg35* [55] [72] I2, c.63-4delC [72] E10, p.Thr294Lys [55] [72] E13, p.Arg482* [55] "
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    ABSTRACT: The Argentinean program was initiated more than a decade ago as the first experience of systematic translational research focused on NCL in Latin America. The aim was to overcome misdiagnoses and underdiagnoses in the region. 216 NCL suspected individuals from 8 different countries and their direct family members. Clinical assessment, enzyme testing, electron microscopy, DNA screening. 1) The study confirmed NCL disease in 122 subjects. Phenotypic studies comprised epileptic seizures and movement disorders, ophthalmology, neurophysiology, image analysis, rating scales, enzyme testing, and electron microscopy, carried out under a consensus algorithm; 2) DNA screening and validation of mutations in genes PPT1 (CLN1), TPP1 (CLN2), CLN3, CLN5, CLN6, MFSD8 (CLN7), and CLN8: characterization of variant types, novel/known mutations and polymorphisms; 3) Progress of the epidemiological picture in Latin America; 4) NCL-like pathology studies in progress. The Translational Research Program was highly efficient in addressing the misdiagnosis/ underdiagnosis in the NCL disorders. The study of "orphan diseases" in a public administrated hospital should be adopted by the health systems, as it positively impacts upon the family's quality of life, the collection of epidemiological data, and triggers research advances. This article is part of a Special Issue entitled: "Current Research on the Neuronal Ceroid Lipofuscinoses (Batten Disease). Copyright © 2015. Published by Elsevier B.V.
    Biochimica et Biophysica Acta 05/2015; 1852(10 Pt B). DOI:10.1016/j.bbadis.2015.05.003 · 4.66 Impact Factor
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    • "The missense mutation c.881C>A (p.T294K) was found in most patients of Romany origin previously studied by Elleder et al. (Elleder et al., 1997). Haplotype analysis of these patients was consistent with the existence of a common founder effect (Kousi et al., 2009). The human CLN8 gene has been located to chromosome 8p23 (Ranta et al., 1999). "
    Novel Aspects on Epilepsy, 10/2011; , ISBN: 978-953-307-678-2
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    • "TPP1 (cDNA FLJ56402, highly similar to tripeptidyl-peptidase 1), also known as CLN2, is a member of the family of serine-carboxyl proteinases and plays a crucial role in lysosomal protein degradation; a deficiency in this enzyme leads to fatal neurodegenerative disease [58]. It is also involved in telomere protection [59]. "
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    ABSTRACT: Cerebrospinal fluid (CSF) has been used for biomarker discovery of neurodegenerative diseases in humans since biological changes in the brain can be seen in this biofluid. Inactivation of A-T-mutated protein (ATM), a multifunctional protein kinase, is responsible for A-T, yet biochemical studies have not succeeded in conclusively identifying the molecular mechanism(s) underlying the neurodegeneration seen in A-T patients or the proteins that can be used as biomarkers for neurologic assessment of A-T or as potential therapeutic targets. In this study, we applied a high-throughput LC/MS-based label-free protein quantification technology to quantitatively characterize the proteins in CSF samples in order to identify differentially expressed proteins that can serve as potential biomarker candidates for A-T. Among 204 identified CSF proteins with high peptide-identification confidence, thirteen showed significant protein expression changes. Bioinformatic analysis revealed that these 13 proteins are either involved in neurodegenerative disorders or cancer. Future molecular and functional characterization of these proteins would provide more insights into the potential therapeutic targets for the treatment of A-T and the biomarkers that can be used to monitor or predict A-T disease progression. Clinical validation studies are required before any of these proteins can be developed into clinically useful biomarkers.
    06/2011; 2011(2090-2166):578903. DOI:10.1155/2011/578903
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