Parathyroid-Specific Deletion Of Hrpt2 In Mice Results In Hypoparathyroidism

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 199-233-Bone Biology
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-199
Jessica Costa-Guda*1, Sarah T Cohen1, Jennifer Acostamadiedo1, Kirsten Saucier1 and Andrew Arnold2
1Univ of Connecticut Health Ctr, Farmington, CT, 2Univ of Connecticut Sch of Med, Farmington, CT
Hyperparathyroidism jaw-tumor syndrome (HPT-JT) is an autosomal dominant disorder manifesting benign or malignant parathyroid tumors, ossifying fibromas of the jaw, uterine tumors and kidney lesions. Individuals with HPT-JT inherit one abnormal copy of the HRPT2 tumor suppressor gene (also called CDC73), encoding parafibromin; tumors from these individuals frequently exhibit somatic inactivation of the second allele. In addition to familial tumors, sporadic parathyroid carcinomas frequently exhibit biallelic inactivation of HRPT2, and mutations of HRPT2 have also been reported in sporadic ossifying fibromas and renal tumors. To study the role of HRPT2 in parathyroid cell proliferation in vivo, we generated mice with a parathyroid-specific deletion of the Hrpt2 gene using the Cre-LoxP system. Genetically-engineered mice in which the Hrpt2 gene is flanked by two loxP sites (Hrpt2-floxed) mice were crossed with transgenic mice in which expression of the Cre recombinase is under control of the parathyroid hormone (PTH) gene promoter. Knockout mice were viable and fertile and were monitored for biochemical alterations at 1-3 month intervals for 24 months. Homozygous knockout mice demonstrated decreased serum calcium (mean 8.3 mg/dl) at all timepoints compared to heterozygous (mean 9.1 mg/dl) or wild type (mean 9.5 mg/dl) animals; 54% of homozygous knockout animals were hypocalcemic with calcium levels 4.9-8.0 mg/dl. Hypocalcemia was accompanied by decreased serum PTH and elevated phosphate levels, consistent with hypoparathyroidism; kidney and liver function were normal. Histologic examination of the parathyroid glands from homozygous knockout mice revealed significantly smaller gland sizes, often accompanied by abnormal morphology. No hypercalcemia or parathyroid hypercellularity was observed at any age. Thus, while postnatally acquired complete loss of HRPT2 causes parathyroid cell proliferation and hyperparathyroidism, such as seen in human HPT-JT, our results in this animal model suggest that earlier, developmentally-imposed complete loss of Hrpt2 can cause a primary defect in parathyroid gland function. Further studies are required to explore the basis for this hypoparathyroid phenotype and its implication that parafibromin may be required for parathyroid gland development in this murine model.

Nothing to Disclose: JC, STC, JA, KS, AA

*Please take note of The Endocrine Society's News Embargo Policy at

Sources of Research Support: NIH Grant  F32 DE021307 awarded to JCG
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