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Molecular and clinical genetic studies of a novel variant of familial hypercalcemia
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
2002 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Familial primary hyperparathyroidism (HPT) is a rare disorder that is treated surgically and mostly occurs in association with tumor-susceptibility syndromes, like multiple endocrine neoplasia and the hyperparathyroidism-jaw tumor syndrome. Familial hypercalciuric hypercalcemia (FHH) is another cause of hereditary hypercalcemia that generally is considered to require no treatment and is genetically and pathophysiologically distinct from HPT. Inactivating mutations in the calcium receptor gene cause FHH, whereas the down-regulated expression of the CaR in HPT never has been coupled to CaR gene mutations.

Family screening revealed a hitherto unknown familial condition with characteristics of both FHH and HPT. The hypercalcemia was mapped to a point mutation in the intracellular domain of the CaR gene that was coupled to relative calcium resistance of the PTH release by transient expression in HEK 294 cells. Unusually radical excision of parathyroid glands was required to normalise the hypercalcemia. The mildly enlarged parathyroid glands displayed hyperplasia with nodular components. Frequent allelic loss on especially 12q was found and contrasts to findings in HPT. Allelic loss was also seen in loci typical for primary HPT like 1p, 6q and 15q, but not 11q13. Quantitative mRNA analysis showed that the glands had mild increase in a proliferation index (PCNA/GAPDH mRNA ratio) and mild reduction in genes important to parathyroid cell function, like CaR, PTH, VDR and LRP2.

A previously unrecognized variant of hypercalcemia is explored that could be one explanation for persistent hypercalcemia after apparently typical routine operations for HPT. It also raises the issue of possibilities to treat FHH with parathyroidectomy provided it is radical enough.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2002. , p. 56
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1147
Keywords [en]
Surgery, hyperparathyroidism, calcium receptor, hypercalcemia, allelic loss, autosomal inheritance
Keywords [sv]
Kirurgi
National Category
Surgery
Research subject
Surgery
Identifiers
URN: urn:nbn:se:uu:diva-2002ISBN: 91-554-5300-7 (print)OAI: oai:DiVA.org:uu-2002DiVA, id: diva2:161615
Public defence
2002-05-16, Hedstrandssalen, Ing 70 bv, Akademiska sjukhuset, Uppsala, 13:15
Opponent
Available from: 2002-04-25 Created: 2002-04-25Bibliographically approved

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