title: Four novel germline mutations in the MLH1 and PMS2 mismatch repair genes in patients with hereditary nonpolyposis colorectal cancer.
abstract: BACKGROUND
  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.
  
  
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  In all patients, an abnormal expression of the MMR proteins in HNPCC was related to the above novel mutations.
authors.affiliation: Research Center for Gastroenterology and Liver Diseases, Taleghani Hospital, Shaheed Beheshti Medical University, Tehran, Iran. mah_haghighi@hotmail.com
authors.forename: Mahdi
authors.initials: M
authors.lastname: Montazer Haghighi
authors.forename: Ramin
authors.initials: R
authors.lastname: Radpour
authors.forename: Katayoun
authors.initials: K
authors.lastname: Aghajani
authors.forename: Narges
authors.initials: N
authors.lastname: Zali
authors.forename: Mahsa
authors.initials: M
authors.lastname: Molaei
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Zali
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis / Q000235:genetics*; D000251:Adenosine Triphosphatases / Q000032:analysis / Q000235:genetics*; D000368:Aged; D018389:Codon, Nonsense; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D053843:DNA Mismatch Repair; D004252:DNA Mutational Analysis; D045643:DNA Repair Enzymes / Q000032:analysis / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics*; D005091:Exons; D005260:Female; D016368:Frameshift Mutation; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D007492:Iran; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics*; D010375:Pedigree
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018389:Codon, Nonsense; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D045643:DNA Repair Enzymes