TY - JOUR
T1 - The hMSH2(M688R) lynch syndrome mutation may function as a dominant negative
AU - Martín-López, Juana V.
AU - Barrios, Ysamar
AU - Medina-arana, Vicente
AU - Andújar, Miguel
AU - Lee, Sanghee
AU - Gu, Liya
AU - Li, Guo Min
AU - Rüschoff, Josef
AU - Salido, Eduardo
AU - Fishel, Richard
N1 - Funding Information:
This work was supported by 28/03 FUNCIS (to E.S. and Y.B.) and National Institutes of Health grants CA104333 (to L.G.) and CA67007 (to R.F.).
PY - 2012/9
Y1 - 2012/9
N2 - 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.
AB - 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.
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U2 - 10.1093/carcin/bgs199
DO - 10.1093/carcin/bgs199
M3 - Article
C2 - 22739024
AN - SCOPUS:84865544805
SN - 0143-3334
VL - 33
SP - 1647
EP - 1654
JO - Carcinogenesis
JF - Carcinogenesis
IS - 9
ER -