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Vitamin D receptor as a candidate tumor-suppressor gene in severe hyperparathyroidism of uremia
S B Brown1, T T Brierley, N Palanisamy
1Center for Molecular Medicine and Division of Endocrinology and Metabolism, University of Connecticut School of Medicine, Farmington 06030-3101, USA.
Abstract:
Most chronic renal failure patients with severe refractory hyperparathyroidism harbor at least one monoclonal parathyroid tumor, but the specific acquired genetic defects that confer this clonal selective advantage remain poorly understood. Somatic inactivation of the vitamin D receptor (VDR) gene could contribute to clonal outgrowth, because a parathyroid cell containing this lesion would have an impaired response to the antiproliferative influence of 1,25-dihydroxyvitamin D3. Furthermore, diminished expression of VDR protein has been described in uremia-associated parathyroid tumors. Therefore, to assess VDR gene inactivation's potential pathogenetic role in this disease, we rigorously analyzed the VDR gene in 59 parathyroid tumors surgically resected from uremic patients. First, Southern blotting and/or PCR analyses of 29 tumor samples from 14 genetically informative patients revealed no allelic losses at the VDR locus. Next, direct DNA sequencing of all VDR splice junctions, associated intronic sequences, and virtually the entire VDR-coding region for all 59 tumors revealed no acquired mutations. Last, 37 tumor DNA samples were subjected to comparative genomic hybridization, and no chromosomal losses in the VDR region (12cen-q12) were observed. These observations suggest that inactivating defects within the VDR gene do not commonly contribute to the primary pathogenesis of severe refractory hyperparathyroidism in uremia.
Insights
Inactivating defects in the vitamin D receptor (VDR) gene are not a common cause of severe refractory hyperparathyroidism in chronic kidney disease patients. This study found no evidence of VDR gene mutations or losses in parathyroid tumors.
Area of Science:
- Nephrology
- Endocrinology
- Molecular Biology
Background:
- Severe refractory hyperparathyroidism in chronic renal failure patients often involves monoclonal parathyroid tumors.
- The genetic causes of clonal expansion in these tumors are not well understood.
- Vitamin D receptor (VDR) gene inactivation and reduced VDR protein expression are hypothesized contributors.
Purpose of the Study:
- To investigate the potential role of VDR gene inactivation in the pathogenesis of severe refractory hyperparathyroidism in uremic patients.
- To analyze VDR gene alterations in parathyroid tumors from patients with chronic renal failure.
Main Methods:
- Analysis of 59 parathyroid tumors from uremic patients.
- Southern blotting, PCR, and direct DNA sequencing of the VDR gene.
- Comparative genomic hybridization (CGH) to assess chromosomal losses in the VDR region.
Main Results:
- No allelic losses at the VDR locus were detected in 29 tumor samples.
- No acquired mutations in the VDR gene were found in 59 tumors.
- Comparative genomic hybridization revealed no chromosomal losses in the VDR region (12cen-q12) in 37 tumors.
Conclusions:
- Inactivating defects within the VDR gene do not appear to be a common primary cause of severe refractory hyperparathyroidism in uremia.
- The study suggests other genetic or molecular mechanisms are likely responsible for clonal parathyroid tumor growth in this condition.