title: Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease.
abstract: Cowden disease, also known as multiple hamartoma syndrome, is an autosomal dominant cancer syndrome with a high risk of breast and thyroid cancer. The gene involved has been localized to chromosome 10q22-23. Recently, the tumour suppressor gene PTEN/MMAC1, encoding a putative protein tyrosine or dual-specificity phosphatase, was cloned from that region 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 mutation analysis in eight unrelated familial and 11 sporadic patients with Cowden disease. Eight different mutations were detected in various regions of the PTEN/MMAC1 gene. One mutation was detected twice. All detected changes in the gene can be predicted to have a very deleterious effect on the putative protein. Five of the nine patients have a mutation in exon 5 coding for the putative active site and flanking amino acids. Evaluation of the clinical data of the patients in which a mutation could be detected gives no clear indications for a correlation between the genotype and phenotype. In 10 patients no mutation could be detected so far. In support of the linkage data, no evidence has emerged from the phenotype of these patients suggestive for genetic heterogeneity.
authors.affiliation: Department of Neurology, University Hospital Nijmegen, The Netherlands.
authors.forename: M R
authors.initials: MR
authors.lastname: Nelen
authors.forename: W C
authors.initials: WC
authors.lastname: van Staveren
authors.forename: E A
authors.initials: EA
authors.lastname: Peeters
authors.forename: M B
authors.initials: MB
authors.lastname: Hassel
authors.forename: R J
authors.initials: RJ
authors.lastname: Gorlin
authors.forename: H
authors.initials: H
authors.lastname: Hamm
authors.forename: C F
authors.initials: CF
authors.lastname: Lindboe
authors.forename: J P
authors.initials: JP
authors.lastname: Fryns
authors.forename: R H
authors.initials: RH
authors.lastname: Sijmons
authors.forename: D G
authors.initials: DG
authors.lastname: Woods
authors.forename: E C
authors.initials: EC
authors.lastname: Mariman
authors.forename: G W
authors.initials: GW
authors.lastname: Padberg
authors.forename: H
authors.initials: H
authors.lastname: Kremer
mesh_terms: D000328:Adult; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10; D004252:DNA Mutational Analysis; D005260:Female; D016147:Genes, Tumor Suppressor; D018095:Germ-Line Mutation; D006223:Hamartoma Syndrome, Multiple / Q000235:genetics*; D006801:Humans; D008297:Male; D051059:PTEN Phosphohydrolase; D010375:Pedigree; D010744:Phosphoric Monoester Hydrolases; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D025521:Tumor Suppressor Proteins
chemical_list: D025521:Tumor Suppressor Proteins; D010744:Phosphoric Monoester Hydrolases; D017027:Protein Tyrosine Phosphatases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human