Functional characterization of MLH1 missense variants identified in Lynch Syndrome patients

Sofie Dabros Andersen; Sascha Emilie Liberti; Anne Lützen; Mark Drost; Inge Bernstein; Mef Nilbert; Mev Dominguez; Minna Nyström; Thomas Van Overeem Hansen; Janus Wiese Christoffersen; Anne Charlotte Jäger; Niels de Wind; Finn Cilius Nielsen; Pernille M Tørring; Lene Juel Rasmussen

doi:10.1002/humu.22153

Functional characterization of MLH1 missense variants identified in Lynch Syndrome patients

Sofie Dabros Andersen, Sascha Emilie Liberti, Anne Lützen, Mark Drost, Inge Bernstein, Mef Nilbert, Mev Dominguez, Minna Nyström, Thomas Van Overeem Hansen, Janus Wiese Christoffersen, Anne Charlotte Jäger, Niels de Wind, Finn Cilius Nielsen, Pernille M Tørring, Lene Juel Rasmussen

14 Citationer (Scopus)

Abstract

Germline mutations in the human DNA mismatch repair (MMR) genes MSH2 and MLH1 are associated with the inherited cancer disorder Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer or HNPCC. A proportion of MSH2 and MLH1 mutations found in suspected LS patients give rise to single amino acid substitutions. The functional consequences in regard to pathogenicity of many of these variants are unclear. We have examined the functionality of a panel of MLH1 missense mutations found in LS families, by testing the variant proteins in functional assays, addressing subcellular localization, and protein-protein interaction with the dimer partner PMS2 and the MMR-associated exonuclease 1. We show that a significant proportion of examined variant proteins have functional defects in either subcellular localization or protein-protein interactions, which is suspected to lead to the cancer phenotype observed in patients. Moreover, the obtained results correlate well with reported MMR activity and with in silico analysis for a majority of the variants.

Originalsprog	Engelsk
Tidsskrift	Human Mutation
Vol/bind	33
Udgave nummer	12
Sider (fra-til)	1647-1655
Antal sider	9
ISSN	1059-7794
DOI	https://doi.org/10.1002/humu.22153
Status	Udgivet - dec. 2012

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Andersen, S. D., Liberti, S. E., Lützen, A., Drost, M., Bernstein, I., Nilbert, M., Dominguez, M., Nyström, M., Hansen, T. V. O., Christoffersen, J. W., Jäger, A. C., de Wind, N., Nielsen, F. C., Tørring, P. M., & Rasmussen, L. J. (2012). Functional characterization of MLH1 missense variants identified in Lynch Syndrome patients. Human Mutation, 33(12), 1647-1655. https://doi.org/10.1002/humu.22153

Andersen, SD, Liberti, SE, Lützen, A, Drost, M, Bernstein, I, Nilbert, M, Dominguez, M, Nyström, M, Hansen, TVO, Christoffersen, JW, Jäger, AC, de Wind, N, Nielsen, FC, Tørring, PM & Rasmussen, LJ 2012, 'Functional characterization of MLH1 missense variants identified in Lynch Syndrome patients', Human Mutation, bind 33, nr. 12, s. 1647-1655. https://doi.org/10.1002/humu.22153

@article{32f887a9f61a4cbcaceef36f8132a6b5,

title = "Functional characterization of MLH1 missense variants identified in Lynch Syndrome patients",

abstract = "Germline mutations in the human DNA mismatch repair (MMR) genes MSH2 and MLH1 are associated with the inherited cancer disorder Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer or HNPCC. A proportion of MSH2 and MLH1 mutations found in suspected LS patients give rise to single amino acid substitutions. The functional consequences in regard to pathogenicity of many of these variants are unclear. We have examined the functionality of a panel of MLH1 missense mutations found in LS families, by testing the variant proteins in functional assays, addressing subcellular localization, and protein-protein interaction with the dimer partner PMS2 and the MMR-associated exonuclease 1. We show that a significant proportion of examined variant proteins have functional defects in either subcellular localization or protein-protein interactions, which is suspected to lead to the cancer phenotype observed in patients. Moreover, the obtained results correlate well with reported MMR activity and with in silico analysis for a majority of the variants.",

author = "Andersen, {Sofie Dabros} and Liberti, {Sascha Emilie} and Anne L{\"u}tzen and Mark Drost and Inge Bernstein and Mef Nilbert and Mev Dominguez and Minna Nystr{\"o}m and Hansen, {Thomas Van Overeem} and Christoffersen, {Janus Wiese} and J{\"a}ger, {Anne Charlotte} and {de Wind}, Niels and Nielsen, {Finn Cilius} and T{\o}rring, {Pernille M} and Rasmussen, {Lene Juel}",

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year = "2012",

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doi = "10.1002/humu.22153",

language = "English",

volume = "33",

pages = "1647--1655",

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TY - JOUR

T1 - Functional characterization of MLH1 missense variants identified in Lynch Syndrome patients

AU - Andersen, Sofie Dabros

AU - Liberti, Sascha Emilie

AU - Lützen, Anne

AU - Drost, Mark

AU - Bernstein, Inge

AU - Nilbert, Mef

AU - Dominguez, Mev

AU - Nyström, Minna

AU - Hansen, Thomas Van Overeem

AU - Christoffersen, Janus Wiese

AU - Jäger, Anne Charlotte

AU - de Wind, Niels

AU - Nielsen, Finn Cilius

AU - Tørring, Pernille M

AU - Rasmussen, Lene Juel

PY - 2012/12

Y1 - 2012/12

N2 - Germline mutations in the human DNA mismatch repair (MMR) genes MSH2 and MLH1 are associated with the inherited cancer disorder Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer or HNPCC. A proportion of MSH2 and MLH1 mutations found in suspected LS patients give rise to single amino acid substitutions. The functional consequences in regard to pathogenicity of many of these variants are unclear. We have examined the functionality of a panel of MLH1 missense mutations found in LS families, by testing the variant proteins in functional assays, addressing subcellular localization, and protein-protein interaction with the dimer partner PMS2 and the MMR-associated exonuclease 1. We show that a significant proportion of examined variant proteins have functional defects in either subcellular localization or protein-protein interactions, which is suspected to lead to the cancer phenotype observed in patients. Moreover, the obtained results correlate well with reported MMR activity and with in silico analysis for a majority of the variants.

AB - Germline mutations in the human DNA mismatch repair (MMR) genes MSH2 and MLH1 are associated with the inherited cancer disorder Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer or HNPCC. A proportion of MSH2 and MLH1 mutations found in suspected LS patients give rise to single amino acid substitutions. The functional consequences in regard to pathogenicity of many of these variants are unclear. We have examined the functionality of a panel of MLH1 missense mutations found in LS families, by testing the variant proteins in functional assays, addressing subcellular localization, and protein-protein interaction with the dimer partner PMS2 and the MMR-associated exonuclease 1. We show that a significant proportion of examined variant proteins have functional defects in either subcellular localization or protein-protein interactions, which is suspected to lead to the cancer phenotype observed in patients. Moreover, the obtained results correlate well with reported MMR activity and with in silico analysis for a majority of the variants.

U2 - 10.1002/humu.22153

DO - 10.1002/humu.22153

M3 - Journal article

C2 - 22753075

SN - 1059-7794

VL - 33

SP - 1647

EP - 1655

JO - Human Mutation

JF - Human Mutation

IS - 12

ER -

Functional characterization of MLH1 missense variants identified in Lynch Syndrome patients

Abstract

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