Functional characterization of MLH1 missense variants identified in Lynch syndrome patients.
Hum Mutat
; 33(12): 1647-55, 2012 Dec.
Article
de En
| MEDLINE
| ID: mdl-22753075
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.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Protéines nucléaires
/
Tumeurs colorectales héréditaires sans polypose
/
Mutation faux-sens
/
Protéines adaptatrices de la transduction du signal
Limites:
Animals
/
Humans
Langue:
En
Journal:
Hum Mutat
Sujet du journal:
GENETICA MEDICA
Année:
2012
Type de document:
Article
Pays d'affiliation:
Danemark