权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Dominant-negative GCMB mutations cause hypoparathyroidism

显性阴性 GCMB 突变导致甲状旁腺功能减退症

基本信息

批准号：
7874711
负责人：
Michael Mannstadt
金额：
$ 15.99万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-15 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7874711
关键词：
Ablation Adult Affect Alleles Amino Acid Sequence Amino Acids Binding Binding Sites Biological Assay Biology C-terminal Calcium Candidate Disease Gene Cell Culture Techniques Cells Data Development Disease Dominant-Negative Mutation Embryonic Development Endocrine System Diseases Etiology Exons Failure Family Family member Future Gene Targeting Gland Goals Homeostasis Homologous Gene Human Hypercalcemia Hyperparathyroidism Hypocalcemia result Hypoparathyroidism In Vitro Incidence Lead Location Luciferases Mus Mutation Neuroglia Nucleic Acid Regulatory Sequences Nucleotides Open Reading Frames Orthologous Gene Parathyroid Hormones Parathyroid gland Patients Peptide Sequence Determination Production Promoter Regions Property Proteins Regulation Reporter Research Research Personnel Role Secondary Hyperparathyroidism Silicon Dioxide Small Interfering RNA Structure Structure of parathyroid chief cell Technology Therapeutic Time Transactivation base bone health bone metabolism calcium phosphate chromatin immunoprecipitation gland development human PTH protein improved loss of function mutation member mutant novel overexpression programs transcription factor

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：