? GCMB is a transcription factor that is exclusively expressed in parathyroid cells and that is necessary for parathyroid gland development. These glands produce parathyroid hormone (PTH), which is one of the most important regulators of calcium homeostasis and bone metabolism. My long-term goal is to elucidate the role(s) of GCMB in the mature parathyroid gland and its potential for use in therapeutic strategies to treat primary and secondary hyperparathyroidism. ? Mice with homozygous ablation of Gcm2, one of the two mammalian orthologs, lack parathyroid glands and develop hypocalcemia and hyperphosphatemia. Consistent with these findings in mice, a homozygous deletion within GCMB, the human homolog of Gcm2, was previously revealed as a cause of an autosomal recessive form of hypoparathyroidism. I have now identified heterozygous GCMB mutations in the affected, but not the unaffected members of two unrelated families with autosomal dominant hypoparathyroidism. Both heterozygous GCMB mutations are single nucleotide deletions within GCMB exon 5 that introduce changes within the C-terminal portion of GCMB, which contains the putative transactivation domain. The deletions lead to a shift in open reading frame at amino acid residues 463 and 467, respectively, and the addition of 65 and 63 amino acids, respectively, of unrelated protein sequence. Preliminary data demonstrate that the mutant forms of GCMB inhibited the actions of the wild-type protein on a luciferase reporter construct in vitro suggesting that the mutant GCMB has dominant-negative properties. ? To explore the underlying mechanisms leading to impaired PTH synthesis and secretion, I will determine the mechanism through which heterozygous GCMB mutations cause autosomal-dominant hypoparathyroidism (Aim 1), using a GCMB-responsive reporter in vitro, and whether the identified dominant-negative GCMB mutants affect PTH synthesis and secretion in primary parathyroid cell cultures (Aim 2). Furthermore, I will investigate additional members of the two families with autosomal dominant hypoparathyroidism, and I will identify the natural target genes for GCMB(Aim 3). ? Parathyroid glands produce parathyroid hormone (PTH), which is necessary for calcium regulation and bone health. In two families with insufficient parathyroid gland activity, we have identified mutations in GCMB, a factor necessary for the development of parathyroid glands. The characterization of these mutations will help improve our understanding of parathyroid gland biology. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08DK081669-01
Application #
7513972
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
2008-07-15
Project End
2013-06-30
Budget Start
2008-07-15
Budget End
2009-06-30
Support Year
1
Fiscal Year
2008
Total Cost
$158,949
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Mannstadt, Michael; Harris, Mark; Bravenboer, Bert et al. (2013) Germline mutations affecting G?11 in hypoparathyroidism. N Engl J Med 368:2532-4
Zhao, W; Petit, E; Gafni, R I et al. (2013) Mutations in NOTCH2 in patients with Hajdu-Cheney syndrome. Osteoporos Int 24:2275-81
Mitchell, Deborah M; Regan, Susan; Cooley, Michael R et al. (2012) Long-term follow-up of patients with hypoparathyroidism. J Clin Endocrinol Metab 97:4507-14
Yi, Hyon-Seung; Eom, Young Sil; Park, Ie Byung et al. (2012) Identification and characterization of C106R, a novel mutation in the DNA-binding domain of GCMB, in a family with autosomal-dominant hypoparathyroidism. Clin Endocrinol (Oxf) 76:625-33
Mannstadt, Michael; Magen, Daniella; Segawa, Hiroko et al. (2012) Fanconi-Bickel syndrome and autosomal recessive proximal tubulopathy with hypercalciuria (ARPTH) are allelic variants caused by GLUT2 mutations. J Clin Endocrinol Metab 97:E1978-86
Mannstadt, Michael; Holick, Emily; Zhao, Wenping et al. (2011) Mutational analysis of GCMB, a parathyroid-specific transcription factor, in parathyroid adenoma of primary hyperparathyroidism. J Endocrinol 210:165-71
Mannstadt, Michael; Bertrand, Guylene; Muresan, Mihaela et al. (2008) Dominant-negative GCMB mutations cause an autosomal dominant form of hypoparathyroidism. J Clin Endocrinol Metab 93:3568-76