Four novel germline mutations in the MLH1 and PMS2 mismatch repair genes in patients with hereditary nonpolyposis colorectal cancer

  • Mahdi Montazer HaghighiEmail author
  • Ramin RadpourEmail author
  • Katayoun Aghajani
  • Narges Zali
  • Mahsa Molaei
  • Mohammad Reza Zali
Original Article



Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common cause of early onset hereditary colorectal cancer. In the majority of HNPCC families, microsatellite instability (MSI) and germline mutation in one of the DNA mismatch repair (MMR) genes are found.

Materials and methods

The entire coding sequence of MMR genes (MLH1, MLH2, MLH6, and PMS2) was analyzed using direct sequencing. Also, tumor tests were done as MSI and immunohistochemistry testing.


We were able to find three novel MLH1 and one novel PMS2 germline mutations in three Iranian HNPCC patients. The first was a transversion mutation c.346A>C (T116P) and happened in the highly conserved HATPase-c region of MLH1 protein. The second was a transversion mutation c.736A>T (I246L), which caused an amino acid change of isoleucine to leucine. The third mutation (c.2145,6 delTG) was frameshift and resulted in an immature stop codon in five codons downstream. All of these three mutations were detected in the MLH1 gene. The other mutation was a transition mutation, c.676G>A (G207E), which has been found in exon six of the PMS2 gene and caused an amino acid change of glycine to glutamic acid. MSI assay revealed high instability in microsatellite for two patients and microsatellite stable for one patient.


In all patients, an abnormal expression of the MMR proteins in HNPCC was related to the above novel mutations.


HNPCC Mismatch repair MMR Microsatellite instability MLH1 PMS2 



We thank Regan Geissmann for proofreading the text, and we are indebted to the patients for their cooperation. This research was supported by grants from the Research Center for Gastroenterology and Liver Diseases, Taleghani Hospital, Shaheed Beheshti Medical University.


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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Mahdi Montazer Haghighi
    • 1
    Email author
  • Ramin Radpour
    • 2
    Email author
  • Katayoun Aghajani
    • 1
  • Narges Zali
    • 1
  • Mahsa Molaei
    • 1
  • Mohammad Reza Zali
    • 1
  1. 1.Research Center for Gastroenterology and Liver DiseasesTaleghani Hospital, Shaheed Beheshti Medical UniversityTehranIran
  2. 2.Laboratory for Prenatal Medicine and Gynecologic Oncology, Women’s Hospital/Department of BiomedicineUniversity of BaselBaselSwitzerland

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