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Editor—Germline mutations in the dual specificity phosphatase genePTEN (also known as MMAC1 orTEP1) have been associated with susceptibility to two related hamartomatous disorders, Cowden syndrome (CS, MIM 158350) and Bannayan-Riley-Ruvalcaba syndrome (BRR, MIM 153480).1 2It has recently been established that PTEN functions as a 3-phosphatase towards phospholipid substrates in the phosphatidylinositol 3-kinase (PI-3 kinase) pathway.3 Lack of PTEN results in the accumulation of phosphatidylinositol-(3,4,5)-P3, which is required for activation of protein kinase B (PKB)/Akt, a downstream target of PI3-kinase and a known cell survival factor.4-8
While up to 81% of CS and approximately 60% of BRR cases have detectable PTEN germline mutations, no mutations in the coding region or exon-intron boundaries of PTEN have been found in the remaining affected subjects.2 9-13Informative PTEN mutation negative families have been shown to be linked to the 10q23 region, where PTENlies,2 14 although recently there has been a report of two CS families in which linkage to 10q23 has been excluded.9 This has raised the possibility that either a regulatory region of the PTEN gene not included in previous studies, such as the promoter region, or another, closely located gene might be responsible for the CS and BRR cases in which noPTEN mutation has been found. The first alternative is unlikely to represent the majority of such cases, as no evidence ofPTEN transcriptional silencing has been detected in …