Locus-specific mutation databases for neurodegenerative brain diseases

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.

Figure 1

Boxplot showing disease onset age distributions per gene. Family-based average onset ages of established pathogenic variants were used. For PARK7, PARK2, and PINK1, only patients carrying homozygous or compound heterozygous mutations were included in the calculations. Boxes represent the interquartile onset age distribution, horizontal lines indicate medians, whiskers show standard deviations, and circles indicate outliers.

Figure 2

Example of graphical presentation of gene mutations. Shown is the example of VCP mutations in the 3D organization of three monomers of the homohexameric protein organization (PDB entry 3CF3). Mutations are shown as red atoms on the ribbon presentation of the CDC48-like N-terminal domain (yellow), and D1 (blue) and D2 (green) ATPase domains, clearly demonstrating the alignment of mutations at the interface between the CDC48 and D1 domains [Weihl et al., 2009].