Locus-Specific Mutation Databases for Neurodegenerative Brain Diseases

Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium.
Human Mutation (Impact Factor: 5.05). 09/2012; 33(9):1340-4. DOI: 10.1002/humu.22117
Source: PubMed

ABSTRACT 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, Aug 16, 2015
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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 · 4.85 Impact Factor
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    • "The mutations are shown with the affected amino acid, the affected APP codon and, if applicable, the amino acid alteration resulting from the mutation. Mutations were found using the Alzheimer Disease and Frontotemporal Dementia Mutation Database ( Cruts et al., 2012 ) and PubMed: 1 ( Lan et al., 2014 ); 2 ( Kaden et al., 2012 ). "
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    ABSTRACT: Abstract Hereditary cerebral hemorrhage with amyloidosis - Dutch type is an autosomal dominant hereditary disease caused by a point mutation in the amyloid precursor protein gene on chromosome 21. The mutation causes an amino acid substitution at codon 693 (E22Q), the 'Dutch mutation'. Amyloid beta, the product after cleavage of the amyloid precursor protein, is secreted into the extracellular space. The Dutch mutation leads to altered amyloid beta cleavage and secretion, enhanced aggregation properties, higher proteolysis resistance, lowered brain efflux transporter affinity, and enhanced cell surfaces binding. All these result in amyloid beta accumulation in cerebral vessel walls, causing cell death and vessel wall integrity loss, making cerebral vessel walls in hereditary cerebral hemorrhage with amyloidosis-Dutch type more prone to rupture and obstruction, leading to hemorrhages and infarcts. Studying the effects of altered amyloid beta metabolism due to mutations like the 'Dutch' provides us with
    Reviews in the neurosciences 05/2014; 25(5). DOI:10.1515/revneuro-2014-0008 · 3.31 Impact Factor
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