Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease |
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Authors: | Nelen MR; van Staveren WC; Peeters EA; Hassel MB; Gorlin RJ; Hamm H; Lindboe CF; Fryns JP; Sijmons RH; Woods DG; Mariman EC; Padberg GW; Kremer H |
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Institution: | Department of Neurology, University Hospital Nijmegen, The Netherlands. |
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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.
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