Journal Article

The <i>hMSH2(M688R)</i> Lynch syndrome mutation may function as a dominant negative

Juana V. Martín-López, Ysamar Barrios, Vicente Medina-Arana, Miguel Andújar, Sanghee Lee, Liya Gu, Guo-Min Li, Josef Rüschoff, Eduardo Salido and Richard Fishel

in Carcinogenesis

Volume 33, issue 9, pages 1647-1654
Published in print September 2012 | ISSN: 0143-3334
Published online June 2012 | e-ISSN: 1460-2180 | DOI:
The hMSH2(M688R) Lynch syndrome mutation may function as a dominant negative

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The hMSH2(M688R) mismatch repair (MMR) gene mutation has been found in five large families from Tenerife, Spain, suggesting it is a Lynch syndrome or hereditary non-polyposis colorectal cancer (LS/HNPCC) founder mutation. In addition to classical LS/HNPCC tumors, these families present with a high incidence of central nervous system (CNS) tumors normally associated with Turcot or constitutional mismatch repair deficiency (CMMR-D) syndromes. Turcot and CMMR-D mutations may be biallelic, knocking out both copies of the MMR gene. The hMSH2(M688R) mutation is located in the ATP hydrolysis (ATPase) domain. We show that the hMSH2(M688R)–hMSH6 heterodimer binds to mismatched nucleotides but lacks normal ATP functions and inhibits MMR in vitro when mixed with the wild-type (WT) heterodimer. Another alteration that has been associated with LS/HNPCC, hMSH2(M688I)–hMSH6, displays no identifiable differences with the WT heterodimer. Interestingly, some extracolonic tumors from hMSH2(M688R) carriers may express hMSH2–hMSH6, yet display microsatellite instability (MSI). The functional analysis along with variability in tumor expression and the high incidence of CNS tumors suggests that hMSH2(M688R) may act as a dominant negative in some tissues, while the hMSH2(M688I) is most likely a benign polymorphism.

Journal Article.  6588 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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