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

TY - JOUR

T1 - Predicting the impact of Lynch syndrome-causing missense mutations from structural calculations

AU - Nielsen, Sofie V.

AU - Stein, Amelie

AU - Dinitzen, Alexander B.

AU - Papaleo, Elena

AU - Tatham, Michael H.

AU - Poulsen, Esben G.

AU - Kassem, Maher M.

AU - Rasmussen, Lene J.

AU - Lindorff-Larsen, Kresten

AU - Hartmann-Petersen, Rasmus

N1 - This work was supported by grants to RHP and KLL from the Danish Cancer Society, the Danish Council for Independent Research (Natural Sciences), the Lundbeck Foundation, the A.P. Møller Foundation for the Advancement of Medical Science, and the Novo Nordisk Foundation. AS is supported by a grant from the Lundbeck Foundation. MHT is supported by a grant from Cancer Research UK.

PY - 2017/4/19

Y1 - 2017/4/19

N2 - 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.

AB - 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.

KW - Journal article

U2 - 10.1371/journal.pgen.1006739

DO - 10.1371/journal.pgen.1006739

M3 - Article

C2 - 28422960

SN - 1553-7390

VL - 13

JO - PLoS Genetics

JF - PLoS Genetics

IS - 4

M1 - e1006739

ER -