Predicting the impact of Lynch syndrome-causing missense mutations from structural calculations.

Abstract:

:Accurate methods to assess the pathogenicity of mutations are needed to fully leverage the possibilities of genome sequencing in diagnosis. Current data-driven and bioinformatics approaches are, however, limited by the large number of new variations found in each newly sequenced genome, and often do not provide direct mechanistic insight. Here we demonstrate, for the first time, that saturation mutagenesis, biophysical modeling and co-variation analysis, performed in silico, can predict the abundance, metabolic stability, and function of proteins inside living cells. As a model system, we selected the human mismatch repair protein, MSH2, where missense variants are known to cause the hereditary cancer predisposition disease, known as Lynch syndrome. We show that the majority of disease-causing MSH2 mutations give rise to folding defects and proteasome-dependent degradation rather than inherent loss of function, and accordingly our in silico modeling data accurately identifies disease-causing mutations and outperforms the traditionally used genetic disease predictors. Thus, in conclusion, in silico biophysical modeling should be considered for making genotype-phenotype predictions and for diagnosis of Lynch syndrome, and perhaps other hereditary diseases.

journal_name

PLoS Genet

journal_title

PLoS genetics

authors

Nielsen SV,Stein A,Dinitzen AB,Papaleo E,Tatham MH,Poulsen EG,Kassem MM,Rasmussen LJ,Lindorff-Larsen K,Hartmann-Petersen R

doi

10.1371/journal.pgen.1006739

subject

Has Abstract

pub_date

2017-04-19 00:00:00

pages

e1006739

issue

4

eissn

1553-7390

issn

1553-7404

pii

PGENETICS-D-16-02385

journal_volume

13

pub_type

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