Familial isolated hypoparathyroidism caused by a mutation in the gene for the transcription factor GCMB
Familial isolated hypoparathyroidism caused by a mutation in the gene for the transcription factor GCMB
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DOI：
10.1172/jci200113180
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发表时间：
2001-10-01
影响因子：
15.9
通讯作者：
Levine, MA
中科院分区：
文献类型：
--
作者：
Ding, CL;Buckingham, B;Levine, MA
甲状旁腺功能减退症的特征是低钙血症、高磷血症和甲状旁腺激素循环浓度缺失或显着降低。转录因子 GCMB 主要（如果不是全部）在甲状旁腺细胞中表达，对于小鼠甲状旁腺的发育至关重要。因此，在本研究中，我们检查了映射到 6p23-24 的 GCMB 基因，作为孤立性甲状旁腺功能减退症的候选基因。我们定义了人类 GCMB 基因的五个外显子的边界，然后在患有孤立性甲状旁腺功能减退症的广泛亲属的先证者的 GCMB 基因中发现了一个大的基因内突变。她的父母和其他几位未受影响的亲戚都是该突变的杂合子。尽管没有任何血缘关系的历史，微卫星分析显示 GCMB 基因侧翼的共享基因型超过 5 cM，这表明先证者的两个 GCMB 等位基因都源自一个共同的祖先。对其他不相关病例的分析没有揭示相同的突变。我们得出的结论是，GCMB 基因的纯合性功能丧失会损害正常的甲状旁腺胚胎学，并导致部分患有该疾病的患者出现孤立的甲状旁腺功能减退症。
Hypoparathyroidism is characterized by hypocalcemia, hyperphosphatemia, and absent or markedly reduced circulating concentrations of parathyroid hormone. The transcription factor GCMB is predominantly, if not exclusively, expressed in parathyroid cells and is critical for development of the parathyroid glands in mice. Thus, in the present study we examined the GCMB gene, mapped to 6p23-24, as a candidate for isolated hypoparathyroidism. We defined the boundaries of the five exons of the human GCMB gene and then identified a large intragenic mutation in the GCMB genes of the proband of an extensive kindred with isolated hypoparathyroidism. Her parents and several other unaffected relatives were heterozygous for the mutation. Despite an absence of any history of consanguinity microsatellite analysis showed shared genotypes that flanked the GCMB gene over a span of 5 cM, suggesting that both of the proband's GCMB alleles had been derived from a single common ancestor. Analysis of additional, unrelated cases did not disclose the same mutation. We conclude that homozygous loss of function of the GCMB gene impairs normal parathyroid gland embryology and is responsible for isolated hypoparathyroidism in a subset of patients with this disease.