Locus-Specific Mutation Databases for Neurodegenerative Brain Diseases

Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium.
Human Mutation (Impact Factor: 5.14). 09/2012; 33(9):1340-4. DOI: 10.1002/humu.22117
Source: PubMed


The Alzheimer disease and frontotemporal dementia (AD&FTLD) and Parkinson disease (PD) Mutation Databases make available curated information of sequence variations in genes causing Mendelian forms of the most common neurodegenerative brain disease AD, frontotemporal lobar degeneration (FTLD), and PD. They are established resources for clinical geneticists, neurologists, and researchers in need of comprehensive, referenced genetic, epidemiologic, clinical, neuropathological, and/or cell biological information of specific gene mutations in these diseases. In addition, the aggregate analysis of all information available in the databases provides unique opportunities to extract mutation characteristics and genotype-phenotype correlations, which would be otherwise unnoticed and unexplored. Such analyses revealed that 61.4% of mutations are private to one single family, while only 5.7% of mutations occur in 10 or more families. The five mutations with most frequent independent observations occur in 21% of AD, 43% of FTLD, and 48% of PD families recorded in the Mutation Databases, respectively. Although these figures are inevitably biased by a publishing policy favoring novel mutations, they probably also reflect the occurrence of multiple rare and few relatively common mutations in the inherited forms of these diseases. Finally, with the exception of the PD genes PARK2 and PINK1, all other genes are associated with more than one clinical diagnosis or characteristics thereof.

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Article: Locus-Specific Mutation Databases for Neurodegenerative Brain Diseases

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    • "In this systematic mutation screen of known dementia genes in 124 subjects with clinical PCA or posterior AD pathology , we investigated 115 variants that have been categorized in AD&FTD ( Cruts et al . , 2012 ) or HPP mutation databases as " pathogenic , " Fig . 1 . Sequence chromatograms from the carriers of the ( A ) PSEN2 Ser130Leu and ( B ) TREM2 Arg47His variants . In both panels ( A ) and ( B ) , the variant site is indicated by the black arrow in the upper chromatogram , whereas the sequence from a control sample lacking the variant i"
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    • "Although functionally essential, FUS LC drives the aggregation of FUS into protein inclusions in vitro and in models of ALS and FTD (Couthouis et al., 2011; Sun et al., 2011). Importantly, five missense or short deletion mutations located within the regions coding for FUS LC are linked to ALS (Belzil et al., 2009; Cruts et al., 2012; Ling et al., 2013; Ticozzi et al., 2009), including G156E, which increases FUS aggregation propensity in vitro and in cell culture (Nomura et al., 2014). Additionally, more than a dozen related sarcomas and leukemias are caused by chromosomal translocations fusing the LC domain of FUS or that of two other human paralogs , RNA-binding protein EWS and TATA-binding protein-associated factor 2N (product of the TAF15 gene), to one of several DNA-binding domains, forming strong transcriptional activators (Riggi et al., 2007). "
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    • "The role of mutant VCP in the pathogenesis of IBMPFD or FTD-ALS remains elusive. So far, 19 pathogenic mutations in VCP have been described (Cruts et al., 2012). The frequency of VCP mutations in FTD is about 1.6%, making it a rare but significant cause of FTD (van der Zee et al., 2009). "
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