Neurodegenerative brain diseases are adult-onset diseases in which degeneration of specific neuronal populations of the central nervous system plays a central role. The most common neurodegenerative brain diseases are Alzheimer disease (AD; MIM# 104300), Parkinson disease (PD; MIM# 168600), and frontotemporal lobar degeneration (FTLD; MIM# 600274) and their prevalence is steadily increasing in the absence of effective therapies. AD, PD, and FTLD are proteinopathies in which the toxic aggregation and deposition of characteristic proteins in specific brain areas are major etiologic and diagnostic hallmarks [Yankner et al., 2008
]. Genetics plays a major role in all three diseases, which in general result from a complex combination of multiple genetic risk and protective factors, in concert with environmental factors constituting an individual's risk to develop the disease at a given point in life. However, AD, FTLD, as well as PD have an infrequent monogenic component in which a highly penetrant Mendelian inherited dominant or recessive mutation invariantly leads to disease, be it often at variable and largely unpredictable ages.
Knowledge of monogenic mutations leading to neurodegenerative brain diseases is of great value for several reasons. In clinical genetic counseling, for example, knowledge of pathological mutations and their genic location will assist in working out efficient diagnostic screening protocols. Moreover, when mutation screening is used to support or specify a clinical diagnosis, a quick survey of parameters such as evidence of familial cosegregation, frequencies of occurrence in patients and unaffected individuals, interspecies codon conservation, cell biological consequences, and genotype–phenotype correlations might assist in making an accurate diagnostic decision prior to treatment. In a research setting, knowledge of the type and location of multiple pathological mutations in a specific disease gene might reveal valuable indications towards functionally critical protein domains and/or motifs and disease mechanisms.
The AD&FTLD and PD Mutation Databases described in this manuscript aim to provide this information for the most commonly mutated genes in a comprehensive way. The AD&FTLD Mutation Database is a locus-specific database (LSDB) that was conceived in 1998 [Cruts and Van Broeckhoven, 1998b
] in the perspective of the Mutation Database Initiative [Cotton et al., 1998
], an initiative originally fostered by the Human Genome Organization (www.hugo-international.org) that has through the years evolved to the Human Genome Variation Society (HGVS, www.hgvs.org). HGVS is dedicated to promoting and supporting of collection, documentation, and free distribution of genomic variation information and associated clinical variations. From the start, the AD&FTLD Mutation Database stores curated genetic, clinical, and biological information of DNA variations in the Mendelian AD genes APP
, and PSEN2
() [Cruts and Van Broeckhoven, 1998a
]. Because of observed genetic overlaps between the etiology of both, AD and FTLD, all known Mendelian FTLD genes () were added to the AD&FTLD Mutation Database from 2004 onward [Gijselinck et al., 2008
; Rademakers et al., 2004
]. The PD Mutation Database was set up in 2010 [Nuytemans et al., 2010
], essentially in response to the lack of comprehensive LSDBs of PD genes. Today, it contains extended genetic and clinical information of variations in the five most common Mendelian PD genes (). The primary user interfaces of the databases are publicly accessible dedicated websites: www.molgen.ua.ac.be/ADMutations and www.molgen.ua.ac.be/FTDMutations for the AD&FTLD Mutation Database, and www.molgen.ua.ac.be/PDmutDB for the PD mutations database. In addition, basic genetic information of the mutations is shared with the Gen2Phen project [Webb et al., 2011
] and NCBI's dbSNP [Sayers et al., 2012
Genes Catalogued in the AD&FTLD and PD Mutation Databases