Mutation screening in the hMLH1 gene in Swedish hereditary nonpolyposis colon cancer families.
Hereditary nonpolyposis colorectal cancer is caused by heritable defects in the DNA mismatch repair genes hMLH1, hMSH2, hPMS1, and hPMS2. We have used denaturing gradient gel electrophoresis to analyze the 19 exons and exon-intron borders of hMLH1 in 39 Swedish hereditary nonpolyposis colorectal cancer families. Germline mutations were found in eight of these families: two splice mutations affecting exons 3 and 7, respectively, and six missense mutations, of which, four were in exon 2 and one each were in exons 1 and 16. The relatively high number of missense mutations raises several important clinical and technical issues. Such alterations can be identified only when using methods that target DNA or mRNA sequence alteration because they do not cause protein truncations detected by in vitro translation assays. Furthermore, the relationship between these missense mutations and the predisposition to colon cancer is difficult to determine without additional information; thus, genetic counseling based on mutation data is difficult.
Tannergård
P
P
Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden.
Lipford
J R
JR
Kolodner
R
R
Frödin
J E
JE
Nordenskjöld
M
M
Lindblom
A
A
D048868:Adaptor Proteins, Signal Transducing; D001483:Base Sequence; D002893:Chromosomes, Human, Pair 3; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000737:chemistry; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D005656:Fungal Proteins / Q000235:genetics*; D005787:Gene Frequency; D005819:Genetic Markers; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D000070957:MutL Protein Homolog 1; D017354:Point Mutation; D011110:Polymorphism, Genetic; D029701:Saccharomyces cerevisiae Proteins; D013548:Sweden
D048868:Adaptor Proteins, Signal Transducing; D017931:DNA Primers; D004273:DNA, Neoplasm; D005656:Fungal Proteins; D005819:Genetic Markers; C088859:MLH1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D000070957:MutL Protein Homolog 1