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. 2010 Feb;31(2):E1126-40.
doi: 10.1002/humu.21152.

A thorough assessment of benign genetic variability in GRN and MAPT

Rita J Guerreiro  1 , Nicole Washecka, John Hardy, Andrew Singleton
Affiliations

A thorough assessment of benign genetic variability in GRN and MAPT

Rita J Guerreiro et al. Hum Mutat. 2010 Feb.

Abstract

Mutations in APP, PSEN1, MAPTand GRNare the most common genetic causes of dementia. The previous miss-assignment of pathogenicity to benign variants in these genes stresses the importance of discerning between disease causing mutations and benign variants with no pathogenic effect on the function of the respective protein. In this study we sequenced GRNand MAPTin 282 samples from the Centre d'Etude du Polymorphisme Humain - Human Genome Diversity Cell Line Panel, in order to identify benign variants that could otherwise be mistaken for pathogenic mutations. We found sixteen different non-synonymous changes, eleven of which are novel variants.

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Figures

Figure 1
Figure 1
Location of non pathogenic, with unclear pathogenicity and pathogenic variants in functional protein domains found in GRN and MAPT according to the AD/FTD database (assessed on March 15th 2009) and including the variants found in the present study.
Figure 2
Figure 2
Location of coding substitutions in functional protein domains, classified as non pathogenic, unclear pathogenicity and pathogenic.
Figure 3
Figure 3
Progranulin sequence alignment of individual granulin domains with conserved cysteine residues highlighted in blue. Pathogenic missense mutations are represented in red, mutations reported as pathogenic [Brouwers, et al., 2008; van der Zee, et al., 2007] or considered as pathogenic in the AD/FTD database [Cruchaga, et al., 2008] are represented in yellow and the variants found in this study are represented in green.
See this image and copyright information in PMC

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