van der Zee, J. et al. A Belgian ancestral haplotype harbours a highly prevalent mutation for 17q21-linked tau-negative FTLD. Brain 129, 841-852

University of Antwerp, Antwerpen, Flemish, Belgium
Brain (Impact Factor: 9.2). 05/2006; 129(Pt 4):841-52. DOI: 10.1093/brain/awl029
Source: PubMed


Among patients with frontotemporal lobar degeneration (FTLD), the respective frequencies of dominant 17q21-linked tau-negative FTLD (with unidentified molecular defect) and 17q21-linked tau-positive FTLD (due to MAPT mutations) remain unknown. Here, in a series of 98 genealogically unrelated Belgian FTLD patients, we identified an ancestral 8 cM MAPT containing haplotype in two patients belonging to multiplex families DR2 and DR8, without demonstrable MAPT mutations, in which FTLD was conclusively linked to 17q21 [maximum summed log of the odds (LOD) score of 5.28 at D17S931]. Interestingly, the same DR2-DR8 ancestral haplotype was observed in five additional familial FTLD patients, indicative of a founder effect. In the FTLD series, the DR2-DR8 ancestral haplotype explained 7% (7 out of 98) of FTLD and 17% (7 out of 42) of familial FTLD and was seven times more frequent than MAPT mutations (1 out of 98 or 1%). Clinically, DR2-DR8 haplotype carriers presented with FTLD often characterized by language impairment, and in one carrier the neuropathological diagnosis was FTLD with rare tau-negative ubiquitin-positive inclusions. Together, these results strongly suggest that the DR2-DR8 founder haplotype at 17q21 harbours a tau-negative FTLD causing mutation that is a much more frequent cause of FTLD in Belgium than MAPT mutations.

Download full-text


Available from: Patrick Santens, Oct 01, 2015
22 Reads
  • Source
    • "2[30], "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Frontotemporal lobar degeneration (FTLD) is a heterogeneous group of neurodegenerative diseases associated with personality changes and progressive dementia. Loss-of-function mutations in the growth factor progranulin (GRN) cause autosomal dominant FTLD, but so far the pathomechanism of sporadic FTLD is unclear. Results We analyzed whether DNA methylation in the GRN core promoter restricts GRN expression and, thus, might promote FTLD in the absence of GRN mutations. GRN expression in human lymphoblast cell lines is negatively correlated with methylation at several CpG units within the GRN promoter. Chronic treatment with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (DAC) strongly induces GRN mRNA and protein levels. In a reporter assay, CpG methylation blocks transcriptional activity of the GRN core promoter. In brains of FTLD patients several CpG units in the GRN promoter are significantly hypermethylated compared to age-matched healthy controls, Alzheimer and Parkinson patients. These CpG motifs are critical for GRN promoter activity in reporter assays. Furthermore, DNA methyltransferase 3a (DNMT3a) is upregulated in FTLD patients and overexpression of DNMT3a reduces GRN promoter activity and expression. Conclusion These data suggest that altered DNA methylation is a novel pathomechanism for FTLD that is potentially amenable to targeted pharmacotherapy.
    05/2013; 1(1). DOI:10.1186/2051-5960-1-16
  • Source
    • "Within the reported GRN mutation carriers with clinical phenotype of PPA [6] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22], the prevalent clinical presentation is the non fluent variant. Only a few single cases with semantic disorders have been reported in association with GRN mutations [24]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Progranulin (GRN) mutations are typically associated with the behavioral variant of frontotemporal dementia and the non-fluent variant of primary progressive aphasia phenotypes. Hereby, we describe a patient affected by semantic variant of primary progressive aphasia (svPPA) with a highly positive family history of dementia, carrying a novel GRN missense variation in exon 11 [g.2897 C > T (p.Thr409Met)], predicted in silico to be damaging to protein structure and function. The variant was absent in 175 frontotemporal lobar degeneration (FTLD) patients and in 38 healthy subjects. This case confirms that GRN represents one of the most frequent FTLD genetic causes, suggesting that a screening is indicated in the case of svPPA presentation.
    Journal of Alzheimer's disease: JAD 04/2013; 36(3). DOI:10.3233/JAD-130317 · 4.15 Impact Factor
  • Source
    • "After the discovery of MAPT as causal gene for FTDP-17, there were still numerous autosomal dominant FTLD cases genetically linked to the same chromosomal region of MAPT (chr17q21), in which no pathogenic mutations had been identified, in spite of an extensive analysis of this gene [36] [37] [38]. A small region rich of genes, localized approximately 6.2 Mb in physical distance to MAPT locus, had been recognized as that one containing the gene responsible for the disease in these families. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Frontotemporal lobar degeneration (FTLD) is one of the most frequent neurodegenerative disorders with a presenile onset. It presents with a spectrum of clinical manifestations, ranging from behavioral and executive impairment to language disorders and motor dysfunction. New diagnostic criteria identified two main cognitive syndromes: behavioral variant frontotemporal dementia (bvFTD) and primary progressive aphasia. Regarding bvFTD, new criteria include the use of biomarkers. According to them, bvFTD can be classified in "possible" (clinical features only), "probable" (inclusion of imaging biomarkers) and "definite" (in the presence of a known causal mutation or at autopsy). Familial aggregation is frequently reported in FTLD, and about 10 % of cases have an autosomal dominant transmission. Microtubule-associated protein tau gene mutations have been the first ones identified, and are generally associated with early onset (40-50 years) and with the bvFTD phenotype. More recently, progranulin gene mutations were recognized in association with the familial form of FTLD and a hexanucleotide repetition in C9ORF72 has been shown to be responsible for familial FTLD and amyotrophic lateral sclerosis. In addition, other genes are linked to rare cases of familiar FTLD. Lastly, a number of genetic risk factors for sporadic forms have also been identified.
    Journal of Neurology 04/2012; 259(3). DOI:10.1007/s00415-012-6507-5 · 3.38 Impact Factor
Show more