TY - JOUR
T1 - Computational and cellular studies reveal structural destabilization and degradation of MLH1 variants in Lynch syndrome
AU - Abildgaard, Amanda B.
AU - Stein, Amelie
AU - Nielsen, Sofie V.
AU - Schultz-Knudsen, Katrine
AU - Papaleo, Elena
AU - Shrikhande, Amruta
AU - Hoffmann, Eva R
AU - Bernstein, Inge
AU - Gerdes, Anne-Marie
AU - Takahashi, Masanobu
AU - Ishioka, Chikashi
AU - Lindorff-Larsen, Kresten
AU - Hartmann-Petersen, Rasmus
N1 - © 2019, Abildgaard et al.
PY - 2019/11
Y1 - 2019/11
N2 - Defective mismatch repair leads to increased mutation rates, and germline loss-of-function variants in the repair component MLH1 cause the hereditary cancer predisposition disorder known as Lynch syndrome. Early diagnosis is important, but complicated by many variants being of unknown significance. Here we show that a majority of the disease-linked MLH1 variants we studied are present at reduced cellular levels. We show that destabilized MLH1 variants are targeted for chaperone-assisted proteasomal degradation, resulting also in degradation of co-factors PMS1 and PMS2. In silico saturation mutagenesis and computational predictions of thermodynamic stability of MLH1 missense variants revealed a correlation between structural destabilization, reduced steady-state levels and loss-of-function. Thus, we suggest that loss of stability and cellular degradation is an important mechanism underlying many MLH1 variants in Lynch syndrome. Combined with analyses of conservation, the thermodynamic stability predictions separate disease-linked from benign MLH1 variants, and therefore hold potential for Lynch syndrome diagnostics.
AB - Defective mismatch repair leads to increased mutation rates, and germline loss-of-function variants in the repair component MLH1 cause the hereditary cancer predisposition disorder known as Lynch syndrome. Early diagnosis is important, but complicated by many variants being of unknown significance. Here we show that a majority of the disease-linked MLH1 variants we studied are present at reduced cellular levels. We show that destabilized MLH1 variants are targeted for chaperone-assisted proteasomal degradation, resulting also in degradation of co-factors PMS1 and PMS2. In silico saturation mutagenesis and computational predictions of thermodynamic stability of MLH1 missense variants revealed a correlation between structural destabilization, reduced steady-state levels and loss-of-function. Thus, we suggest that loss of stability and cellular degradation is an important mechanism underlying many MLH1 variants in Lynch syndrome. Combined with analyses of conservation, the thermodynamic stability predictions separate disease-linked from benign MLH1 variants, and therefore hold potential for Lynch syndrome diagnostics.
U2 - 10.7554/eLife.49138
DO - 10.7554/eLife.49138
M3 - Journal article
C2 - 31697235
SN - 2050-084X
VL - 8
JO - eLife
JF - eLife
M1 - e49138
ER -
