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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Available from: Christine Van Broeckhoven
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    • "Most of these pathogenic alterations are characterized as nonsense, frameshift and splice site mutations causing a premature stop codon, even if other mechanisms have also been observed (Ghidoni et al., 2008;Gass et al., 2012). All pathogenic mutations identified cause disease by protein haploinsufficiency (Baker et al., 2006;Ghidoni et al., 2008;Finch et al., 2009;Sleegers et al., 2009;Cruts et al., 2012) leading to a ∼50% or greater decrease in progranulin levels in the blood, unaffected brain regions and CSF of GRN mutated subjects (Coppola et al., 2008;Ghidoni et al., 2008Ghidoni et al., , 2012Finch et al., 2009;Sleegers et al., 2009). Furthermore, circulating progranulin levels have been proposed as a useful biomarker for a quick and inexpensive largescale screening of GRN mutation carriers (Ghidoni et al., 2012). "
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    ABSTRACT: The overlap of symptoms between neurodegenerative and psychiatric diseases has been reported. Neuropsychiatric alterations are commonly observed in dementia, especially in the behavioral variant of frontotemporal dementia (bvFTD), which is the most common clinical FTD subtype. At the same time, psychiatric disorders, like schizophrenia, can display symptoms of dementia, including features of frontal dysfunction with relative sparing of memory. In the present review we discuss common molecular features in these pathologies with a special focus on FTD. Molecules like Brain Derived Neurotrophic Factor (BDNF) and progranulin are linked to the pathophysiology of both neurodegenerative and psychiatric diseases. In these brain-associated illnesses, the presence of disease-associated variants in BDNF and progranulin (GRN) genes cause a reduction of circulating proteins levels, through alterations in proteins expression or secretion. For these reasons, we believe that prevention and therapy of psychiatric and neurological disorders could be achieved enhancing both BDNF and progranulin levels thanks to drug discovery efforts.
    Full-text · Article · Feb 2016 · Frontiers in Aging Neuroscience
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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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    ABSTRACT: Posterior cortical atrophy (PCA) is an understudied visual impairment syndrome most often due to "posterior Alzheimer's disease (AD)" pathology. Case studies detected mutations in PSEN1, PSEN2, GRN, MAPT, and PRNP in subjects with clinical PCA. To detect the frequency and spectrum of mutations in known dementia genes in PCA, we screened 124 European-American subjects with clinical PCA (n = 67) or posterior AD neuropathology (n = 57) for variants in genes implicated in AD, frontotemporal dementia, and prion disease using NeuroX, a customized exome array. Frequencies in PCA of the variants annotated as pathogenic or potentially pathogenic were compared against ∼4300 European-American population controls from the NHLBI Exome Sequencing Project. We identified 2 rare variants not previously reported in PCA, TREM2 Arg47His, and PSEN2 Ser130Leu. No other pathogenic or potentially pathogenic variants were detected in the screened dementia genes. In this first systematic variant screen of a PCA cohort, we report 2 rare mutations in TREM2 and PSEN2, validate our previously reported APOE ε4 association, and demonstrate the utility of NeuroX.
    Full-text · Article · Oct 2015 · Neurobiology of aging
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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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    ABSTRACT: Phase-separated states of proteins underlie ribonucleoprotein (RNP) granules and nuclear RNA-binding protein assemblies that may nucleate protein inclusions associated with neurodegenerative diseases. We report that the N-terminal low-complexity domain of the RNA-binding protein Fused in Sarcoma (FUS LC) is structurally disordered and forms a liquid-like phase-separated state resembling RNP granules. This state directly binds the C-terminal domain of RNA polymerase II. Phase-separated FUS lacks static structures as probed by fluorescence microscopy, indicating they are distinct from both protein inclusions and hydrogels. We use solution nuclear magnetic resonance spectroscopy to directly probe the dynamic architecture within FUS liquid phase-separated assemblies. Importantly, we find that FUS LC retains disordered secondary structure even in the liquid phase-separated state. Therefore, we propose that disordered protein granules, even those made of aggregation-prone prion-like domains, are dynamic and disordered molecular assemblies with transiently formed protein-protein contacts.
    Full-text · Article · Oct 2015 · Molecular cell
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