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Phenotype of Parathyroid-targeted Cdc73 Deletion in Mice Is Strain-dependent
Jessica Costa-Guda1,2, Sarah T Cohen1, Robert Romano1
1Center for Molecular Oncology, University of Connecticut School of Medicine, Farmington, CT 06030-3101, USA.
Abstract:
Hyperparathyroidism jaw-tumor syndrome is an autosomal dominant disorder caused by mutations in the CDC73/HRPT2 tumor suppressor gene, encoding parafibromin, and manifesting benign or malignant parathyroid tumors, ossifying jaw fibromas, uterine tumors, and kidney lesions. Sporadic parathyroid carcinomas also frequently exhibit inactivating CDC73 mutations and loss of parafibromin. To study the role of CDC73 in parathyroid cell proliferation in vivo, we generated mice with a parathyroid-specific deletion of Cdc73. Homozygous knockout mice on a mixed B6/129/CD1 background had decreased serum calcium and PTH and smaller parathyroid glands compared with heterozygous or wild-type littermates, whereas homozygous Cdc73-null mice on other backgrounds exhibited no abnormalities in parathyroid gland function or development. No hypercalcemia or parathyroid hypercellularity was observed in mice of any background examined at any age. Thus, although postnatally acquired complete loss of CDC73 causes parathyroid cell proliferation and hyperparathyroidism, such as seen in human hyperparathyroidism jaw-tumor syndrome, our results suggest that earlier, developmentally imposed complete loss of Cdc73 can cause a primary defect in parathyroid gland structure/function in a strain-dependent manner. This striking disparity in parathyroid phenotype related to genetic background offers a unique opportunity in an in vivo model system to precisely dissect and identify the responsible molecular mechanisms.
Insights
Loss of the CDC73 gene causes parathyroid tumors in humans. Mouse studies show developmental loss of Cdc73 impacts parathyroid glands, but the effect varies by genetic background.
Area of Science:
- Endocrinology
- Oncology
- Genetics
Background:
- Hyperparathyroidism jaw-tumor syndrome (HPT-JT) is an autosomal dominant disorder linked to mutations in the CDC73/HRPT2 tumor suppressor gene, causing various tumors.
- Sporadic parathyroid carcinomas also frequently show inactivating CDC73 mutations and loss of parafibromin, highlighting CDC73's role in parathyroid tumorigenesis.
Purpose of the Study:
- To investigate the in vivo role of the CDC73 gene in parathyroid cell proliferation and gland development.
- To understand how developmental versus acquired loss of CDC73 function affects parathyroid homeostasis.
Main Methods:
- Generation of mice with parathyroid-specific deletion of the Cdc73 gene (parathyroid-specific knockout).
- Analysis of parathyroid gland structure, function (serum calcium, PTH levels), and tumor development in homozygous and heterozygous Cdc73 knockout mice across different genetic backgrounds (e.g., B6/129/CD1).
Main Results:
- Homozygous Cdc73 knockout mice on a mixed B6/129/CD1 background exhibited reduced serum calcium and PTH, and smaller parathyroid glands.
- In contrast, homozygous Cdc73-null mice on other genetic backgrounds showed no abnormalities in parathyroid gland function or development.
- No hypercalcemia or parathyroid hypercellularity was observed in any examined mice, regardless of background or age.
Conclusions:
- Postnatal loss of CDC73 function can induce parathyroid cell proliferation and hyperparathyroidism, mirroring human HPT-JT syndrome.
- Developmentally imposed complete loss of Cdc73 function can lead to primary defects in parathyroid gland structure and function, with significant strain-dependent variability.
- The observed genetic background-dependent disparity in the parathyroid phenotype provides a valuable in vivo model for dissecting the molecular mechanisms underlying CDC73 function.
