Computational and cellular studies reveal structural destabilization and degradation of MLH1 variants in Lynch syndrome

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Computational and cellular studies reveal structural destabilization and degradation of MLH1 variants in Lynch syndrome. / Abildgaard, Amanda B.; Stein, Amelie; Nielsen, Sofie V.; Schultz-Knudsen, Katrine; Papaleo, Elena; Shrikhande, Amruta; Hoffmann, Eva R; Bernstein, Inge; Gerdes, Anne-Marie; Takahashi, Masanobu; Ishioka, Chikashi; Lindorff-Larsen, Kresten; Hartmann-Petersen, Rasmus.

I: eLife, Bind 8, e49138 , 2019.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

Harvard

Abildgaard, AB, Stein, A, Nielsen, SV, Schultz-Knudsen, K, Papaleo, E, Shrikhande, A, Hoffmann, ER, Bernstein, I, Gerdes, A-M, Takahashi, M, Ishioka, C, Lindorff-Larsen, K & Hartmann-Petersen, R 2019, 'Computational and cellular studies reveal structural destabilization and degradation of MLH1 variants in Lynch syndrome', eLife, bind 8, e49138 . https://doi.org/10.7554/eLife.49138

APA

Abildgaard, A. B., Stein, A., Nielsen, S. V., Schultz-Knudsen, K., Papaleo, E., Shrikhande, A., ... Hartmann-Petersen, R. (2019). Computational and cellular studies reveal structural destabilization and degradation of MLH1 variants in Lynch syndrome. eLife, 8, [e49138 ]. https://doi.org/10.7554/eLife.49138

Vancouver

Abildgaard AB, Stein A, Nielsen SV, Schultz-Knudsen K, Papaleo E, Shrikhande A o.a. Computational and cellular studies reveal structural destabilization and degradation of MLH1 variants in Lynch syndrome. eLife. 2019;8. e49138 . https://doi.org/10.7554/eLife.49138

Author

Abildgaard, Amanda B. ; Stein, Amelie ; Nielsen, Sofie V. ; Schultz-Knudsen, Katrine ; Papaleo, Elena ; Shrikhande, Amruta ; Hoffmann, Eva R ; Bernstein, Inge ; Gerdes, Anne-Marie ; Takahashi, Masanobu ; Ishioka, Chikashi ; Lindorff-Larsen, Kresten ; Hartmann-Petersen, Rasmus. / Computational and cellular studies reveal structural destabilization and degradation of MLH1 variants in Lynch syndrome. I: eLife. 2019 ; Bind 8.

Bibtex

@article{cd18ddc994074b2aa0c660419c020321,
title = "Computational and cellular studies reveal structural destabilization and degradation of MLH1 variants in Lynch syndrome",
abstract = "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.",
author = "Abildgaard, {Amanda B.} and Amelie Stein and Nielsen, {Sofie V.} and Katrine Schultz-Knudsen and Elena Papaleo and Amruta Shrikhande and Hoffmann, {Eva R} and Inge Bernstein and Anne-Marie Gerdes and Masanobu Takahashi and Chikashi Ishioka and Kresten Lindorff-Larsen and Rasmus Hartmann-Petersen",
note = "{\circledC} 2019, Abildgaard et al.",
year = "2019",
doi = "10.7554/eLife.49138",
language = "English",
volume = "8",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications Ltd.",

}

RIS

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

Y1 - 2019

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

VL - 8

JO - eLife

JF - eLife

SN - 2050-084X

M1 - e49138

ER -

ID: 230037288