Mutation analysis of the PTEN / MMAC1 gene in Japanese patients with Cowden disease.

Cowden disease (CD), also known as multiple hamartoma syndrome, is an autosomal dominant cancer syndrome associated with high risk of breast and thyroid cancer. Recently, germline mutations in PTEN / MMAC1, which has nine exons encoding a dual specificity phosphatase with homology to tensin and auxilin, have been identified on chromosome 10q23 in some 40 to 80% of CD patients. Our polymerase chain reaction amplification and sequence analysis of all coding regions identified five different mutations including four novel germline mutations among 5 of 12 unrelated Japanese CD patients. The novel findings included a missense mutation (G --> T) at nucleotide 1004 in exon 8 resulting in an arginine-to-leucine change at codon 335 (R335L), two novel splice-site mutations (209 + 1delGT and 209 + 1delGTAA) in intron 3, and insertion of G at nucleotide 632 in exon 6 (632insG). We also detected a nonsense mutation (C --> T) at nucleotide 697 producing R233X in exon 7, which has been reported previously. From reported phenotypic data concerning CD patients from five different families who had the R233X mutation, it may be suggested that R233X mutation correlates with macrocephaly. Although previous reports have implicated exon 5 as a "hot spot," we found no mutation in exon 5.