RT Journal Article
SR Electronic
T1 Computational and cellular studies reveal structural destabilization and degradation of MLH1 variants in Lynch syndrome
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 622266
DO 10.1101/622266
A1 Amanda B. Abildgaard
A1 Amelie Stein
A1 Sofie V. Nielsen
A1 Katrine Schultz-Knudsen
A1 Elena Papaleo
A1 Amruta Shrikhande
A1 Eva R. Hoffmann
A1 Inge Bernstein
A1 Anne-Marie Gerdes
A1 Masanobu Takahashi
A1 Chikashi Ishioka
A1 Kresten Lindorff-Larsen
A1 Rasmus Hartmann-Petersen
YR 2019
UL http://biorxiv.org/content/early/2019/10/13/622266.abstract
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.