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, Oct 06, 2015
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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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    ABSTRACT: Frontotemporal dementia (FTD) is a genetically and pathologically heterogeneous disorder characterized by personality changes, language impairment, and deficits of executive functions associated with frontal and temporal lobe degeneration. Different phenotypes have been defined on the basis of presenting clinical symptoms, i.e., the behavioral variant of FTD, the agrammatic variant of primary progressive aphasia, and the semantic variant of PPA. Some patients have an associated movement disorder, either parkinsonism, as in progressive supranuclear palsy and corticobasal syndrome, or motor neuron disease (FTD–MND). A family history of dementia is found in 40% of cases of FTD and about 10% have a clear autosomal-dominant inheritance. Genetic studies have identified several genes associated with monogenic FTD: microtubule-associated protein tau, progranulin, TAR DNA-binding protein 43, valosin-containing protein, charged multivesicular body protein 2B, fused in sarcoma, and the hexanucleotide repeat expansion in intron 1 of the chromosome 9 open reading frame 72. Patients often present with an extensive phenotypic variability, even among different members of the same kindred carrying an identical disease mutation. The objective of the present work is to review and evaluate available literature data in order to highlight recent advances in clinical, biological, and neuroimaging features of monogenic frontotemporal lobar degeneration and try to identify different mechanisms underlying the extreme phenotypic heterogeneity that characterizes this disease.
    Frontiers in Aging Neuroscience 09/2015; 7(171). DOI:10.3389/fnagi.2015.00171 · 4.00 Impact Factor
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    • "Todate,69differentGRNmutationshavebeendiscovered in231families(Crutsetal.,2012).Alistofdetailedpathogenic mutationsarereportedin "
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    ABSTRACT: Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by degeneration of the fronto temporal lobes and abnormal protein inclusions. It exhibits a broad clinicopathological spectrum and has been linked to mutations in seven different genes. We will provide a picture, which connects the products of these genes, albeit diverse in nature and function, in a network. Despite the paucity of information available for some of these genes, we believe that RNA processing and post-transcriptional regulation of gene expression might constitute a common theme in the network. Recent studies have unraveled the role of mutations affecting the functions of RNA binding proteins and regulation of microRNAs. This review will combine all the recent findings on genes involved in the pathogenesis of FTD, highlighting the importance of a common network of interactions in order to study and decipher the heterogeneous clinical manifestations associated with FTD. This approach could be helpful for the research of potential therapeutic strategies.
    Frontiers in Molecular Neuroscience 03/2015; 8:9. DOI:10.3389/fnmol.2015.00009 · 4.08 Impact Factor
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    • "The codon 233 of PSEN1 seems to be a hot spot for mutation, as 3 other mutations at codon 233 (p.M233V, p.M233I, and p.M233T) have been reported (Campion et al., 1999; Guerreiro et al., 2010; Houlden et al., 2001; Park et al., 2008; Portet et al., 2003; Raux et al., 2005). All these mutations were described as pathogenic mutations according to the AD and FTDMDB database (Cruts et al., 2012). "
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    ABSTRACT: Early-onset familial Alzheimer's disease (EOFAD) is characterized by the onset of dementia symptoms before 65 years, positive family history, high genetic predisposition, and an autosomal dominant inheritance. We aimed to investigate mutations and to characterize phenotypes in Chinese EOFAD families. Detailed clinical assessments and genetic screening for mutations in the presenilin 1 (PSEN1), presenilin 2, amyloid precursor protein, and APOE genes were carried out in 4 EOFAD families. Two PSEN1 mutations (p.R352C and p.M233L) were identified in 2 EOFAD families, respectively. Mutation p.M233L was associated with prominent very early onset, rapidly progressive dementia, and neurologic symptoms, whereas p.R352C was associated with a progressive dementia, psychiatric syndrome, and chronic disease course. Both mutations are predicted to be pathogenic. Our results showed that mutations in PSEN1 gene might be common in Chinese EOFAD families. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neurobiology of Aging 12/2014; 36(3). DOI:10.1016/j.neurobiolaging.2014.11.009 · 5.01 Impact Factor
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