A novel loss-of-function mutation (N48K) in the PTEN gene in a Spanish patient with Cowden disease.

Cowden disease, also known as multiple hamartoma syndrome, is a rare disease inherited in an autosomal dominant pattern, which confers a high risk of developing breast and thyroid carcinomas. Mutations in PTEN, a tumor suppressor gene located on chromosome 10q23, have been identified in patients with Cowden disease. In this work, the direct sequencing of all coding regions of the PTEN gene led us to the identification of N48K, a new germline PTEN missense mutation, in a patient suffering from Cowden disease. The genetic analysis of 200 chromosomes from healthy individuals revealed that the variant was not common in our population. Moreover, by functional analysis we found that the ability of PTEN N48K mutant protein to inhibit the activation of the proto-oncogene PKB/Akt was impaired, supporting the involvement of N48K mutation in Cowden disease. Loss of heterozygosity using three microsatellites (D10S215, D10S541, and D10S564) and the complete sequence analysis of PTEN exons in breast and endometrial tumor samples from the same patient were also carried out in an attempt to identify additional PTEN somatic mutations. The lack of loss of heterozygosity or additional mutations in tumor samples suggests that abnormalities of the regulatory regions of the PTEN gene or haplo-insufficiency might occur in tumors from Cowden disease patients.