Primary hyperparathyroidism (pHPT) is a pathology associated with one or multiple hyperfunctioning parathyroid glands.  The disease prevalence occurs in roughly 1-2% of the population primarily post-menopausal women.  The molecular pathology of the disease is poorly understood.  Elevated serum calcium levels in the setting of an inappropriately elevated parathyroid hormone level are indicative of the disease process.  The ultimate treatment of the disease is to remove the hyperfunctioning gland. The aim of this thesis was to examine potential genetic and epigenetic aberrations that are potentially disease causing. The methylation signature of normal and pathological parathyroid tissue has yet to be investigated.  DNA was bisulphite modified and analyzed using the Infinium HumanMethylation27 BeadChip. Distinct hierarchical clustering of genes with altered DNA methylation profiles in normal and pathologic parathyroid tissue was evident.  DNA hypermethylation of CDKN2B, CDKN2A, WT1, SFRP1, SFRP2, and SFRP4 known to be important in the development of parathyroid tumors were associated with reduced gene expression in both benign and malignant parathyroid tumors. Familial primary hyperparathyroidism (FPHPT) may occur due to an underlying germ-line mutation in the MEN1, CASR, or HRPT2/CDC73 genes.  Eighty-six young (≤45 years of age) patients with clinically non-syndromic PHPT underwent genetic analysis.  Eight of 86 (9.3%) young patients with clinically non-familial PHPT displayed deleterious germ-line mutations in the susceptibility genes (4 MEN1, 3 CASR, and 1 HRPT2/ CDC73). Accumulation of non-phosphorylated active β -catenin has been reported to commonly occur in parathyroid adenomas from patients with primary hyperparathyroidism (pHPT).  We assessed possible β-catenin stabilizing mutations in a large series of parathyroid adenomas. A total of one hundred and eighty sporadic parathyroid adenomas were examined for mutations in exon 3 of the CTNNB1gene. The mutation S33C (TCT >TGT) was detected by direct-DNA sequencing of PCR fragments in 1 out of 180 sporadic parathyroid adenomas (0.68 %). Eight matched tumor-constitutional DNA pairs from patients with sporadic parathyroid adenomas underwent whole-exome capture and high-throughput sequencing.  Four of eight tumors displayed a frame shift deletion or nonsense mutations within the MEN1 gene, which was accompanied by loss of heterozygosity of the remaining wild-type allele.  One tumor harbored a Y641N mutation of the histone methyltransferase EZH2 gene, previously linked to myeloid and lymphoid malignancy formation. Targeted sequencing in the additional 185 parathyroid adenomas revealed a high rate of MEN1 mutations (35%).

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Diss. (sammanfattning) Uppsala : Univ., 2004. / Härtill 4 uppsatser.

Thesis (M.S.)--Virginia Polytechnic Institute and State University, 1994. / Vita. Abstract. Includes bibliographical references (leaves 38-46). Also available via the Internet.

Thesis (M.S.)--University of Wisconsin--Madison, 1965. / eContent provider-neutral record in process. Description based on print version record. Bibliography: l. 31-33.

Thesis (M.S.)--University of Wisconsin--Madison, 1965. / eContent provider-neutral record in process. Description based on print version record. Bibliography: l. 29-31.

No description available.

Osterix (Osx) is a transcription factor required for osteoblast differentiation and bone formation. We previously demonstrated that continuous parathyroid hormone (PTH) treatment inhibited Osx expression in murine calvaria and osteoblastic UMR106-01 cells through the regulation of two regions on the Osx promoter. Mutational analysis of transcription factor elements within these regions revealed two "Sp-sites" were vital for Osx promoter activity. Blockage of these Sp-sites with Mithramycin A demonstrated their importance for Osx expression. Osx bound to its own promoter at these sites, while PTH treatment inhibited this association. PTH regulation of Osx expression in vivo was investigated in mice by: daily injection of PTH for 3 days, continuous infusion of PTH from osmotic pumps for 14 days, or mice fed a calcium-deficient diet for 21 days. Osx expression was decreased by daily injection, while Osx expression was stimulated in mice receiving continuous PTH infusion and mice fed a calcium-deficient diet.

Osterix (Osx) is a transcription factor required for osteoblast differentiation and bone formation. We previously demonstrated that continuous parathyroid hormone (PTH) treatment inhibited Osx expression in murine calvaria and osteoblastic UMR106-01 cells through the regulation of two regions on the Osx promoter. Mutational analysis of transcription factor elements within these regions revealed two "Sp-sites" were vital for Osx promoter activity. Blockage of these Sp-sites with Mithramycin A demonstrated their importance for Osx expression. Osx bound to its own promoter at these sites, while PTH treatment inhibited this association. PTH regulation of Osx expression in vivo was investigated in mice by: daily injection of PTH for 3 days, continuous infusion of PTH from osmotic pumps for 14 days, or mice fed a calcium-deficient diet for 21 days. Osx expression was decreased by daily injection, while Osx expression was stimulated in mice receiving continuous PTH infusion and mice fed a calcium-deficient diet.