GERMLINE MUTATIONS IN THE PTEN MMAC1 GENE IN PATIENTS WITH COWDEN-DISEASE/

Cowden disease, also known as multiple hamartoma syndrome, is an autos omal dominant cancer syndrome with a high risk of breast and thyroid c ancer, The gene involved has been localized to chromosome 10q22-23. Re cently, the tumour suppressor gene PTEN/MMAC1, encoding a putative pro tein tyrosine or dual-specificity phosphatase, was cloned from that re gion and three mutations were detected in patients with Cowden disease , We confirmed that the PTEN/MMAC1 gene is indeed the gene for Cowden disease by a refined localization of the gene to the interval between D10S1761 and D10S541, which contains the PTEN/MMAC1 gene and by mutati on analysis in eight unrelated familial and 11 sporadic patients with Cowden disease. Eight different mutations were detected in various reg ions of the PTEN/MMAC1 gene, One mutation was detected twice, All dete cted changes in the gene can be predicted to have a very deleterious e ffect on the putative protein, Five of the nine patients have a mutati on in exon 5 coding for the putative active site and flanking amino ac ids. Evaluation of the clinical data of the patients in which a mutati on could be detected gives no clear indications for a correlation betw een the genotype and phenotype, In 10 patients no mutation could be de tected so far, In support of the linkage data, no evidence has emerged from the phenotype of these patients suggestive for genetic heterogen eity.