印记和骨骼疾病:假性甲状旁腺功能低下和相关疾病的教训。

IF 5.9 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Yorihiro Iwasaki, Murat Bastepe
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引用次数: 0

摘要

假性甲状旁腺功能减退症(PHP)最初被描述为一种以甲状旁腺激素(PTH)抵抗合并骨骼异常为特征的综合征,即奥尔布赖特遗传性骨营养不良症(AHO)。此后的研究主要集中在PHP和相关疾病的遗传或表观遗传改变上。刺激G蛋白(Gsα)的α-亚基介导G蛋白偶联受体的信号传导,刺激cAMP的产生。Gsα-cAMP级联对人类骨骼生长至关重要,在与who重叠的骨骼发育不良谱系中,这一信号通路上聚集的致病性突变证明了这一点。编码gsa α的基因GNAS受基因组印记的影响,这是一种通过差异甲基化控制等位基因特异性基因表达的表观遗传机制。亲本等位基因对gsa α表达的贡献在不同组织中存在差异。虽然gsa α在大多数组织(包括骨和软骨)中呈双等位基因转录,但父系gsa α等位基因在有限数量的细胞/组织中被抑制,包括近端肾小管,甲状旁腺激素在其中发挥关键作用。因此,根据受影响亲本等位基因的不同,gsa α突变会导致不同的临床表现。母体突变导致PHP 1A型,由PTH抗性和who组成,父本突变导致伪伪甲状旁腺功能低下(PPHP),即无激素抗性的who。GNAS的表观遗传改变导致PHP1B型(PHP1B),在没有who的情况下由PTH抗性定义。因此,基因组印迹在与GNAS改变相关的表型中起着关键作用。对PHP1B遗传原因的研究已经确定了GNAS的关键印迹控制区,其功能直到最近才通过人类胚胎干细胞模型来阐明早期胚胎的印迹调控机制。我们在此回顾目前对PHP和相关疾病的遗传和表观遗传基础的理解,重点是他们的骨骼表现。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Imprinting and skeletal disorders: Lessons from Pseudohypoparathyroidism and Related Disorders.

Pseudohypoparathyroidism (PHP) was first described as a syndrome characterized by parathyroid hormone (PTH) resistance combined with skeletal abnormalities known as Albright's hereditary osteodystrophy (AHO). Studies have since focused on genetic or epigenetic alterations underlying PHP and related disorders. The α-subunit of the stimulatory G protein (Gsα) mediates the signaling of G protein-coupled receptors that stimulate cAMP generation. The Gsα-cAMP cascade is pivotal for human skeletal growth, as evidenced by pathogenic mutations converging on this signaling pathway in a spectrum of skeletal dysplasias that overlap with AHO. The gene encoding Gsα, GNAS, is subject to genomic imprinting, an epigenetic mechanism governing allele-specific gene expression through differential methylation. Parental allele contribution to Gsα expression differs among tissues. While Gsα is biallelically transcribed in most tissues, including bone and cartilage, the paternal Gsα allele is suppressed in a limited number of cells/tissues, including the proximal renal tubule, where PTH exerts critical actions. Therefore, Gsα mutations cause distinct clinical manifestations according to the affected parental allele. While maternal mutations result in PHP type 1A, which consists of PTH resistance and AHO, paternal mutations lead to pseudo-pseudohypoparathyroidism (PPHP), ie, AHO without hormone resistance. Epigenetic alterations of GNAS cause PHP type 1B (PHP1B), defined by PTH resistance in the absence of AHO. Thus, genomic imprinting plays a key role in the phenotypes associated with GNAS alterations. Investigations on the genetic cause of PHP1B have identified crucial imprinting control regions of GNAS, whose functions were elucidated only recently using human embryonic stem cells to model imprinting regulatory mechanisms in the early embryo. We herein review the current understanding of the genetic and epigenetic basis of PHP and related disorders, focusing on their skeletal manifestations.

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来源期刊
Journal of Bone and Mineral Research
Journal of Bone and Mineral Research 医学-内分泌学与代谢
CiteScore
11.30
自引率
6.50%
发文量
257
审稿时长
2 months
期刊介绍: The Journal of Bone and Mineral Research (JBMR) publishes highly impactful original manuscripts, reviews, and special articles on basic, translational and clinical investigations relevant to the musculoskeletal system and mineral metabolism. Specifically, the journal is interested in original research on the biology and physiology of skeletal tissues, interdisciplinary research spanning the musculoskeletal and other systems, including but not limited to immunology, hematology, energy metabolism, cancer biology, and neurology, and systems biology topics using large scale “-omics” approaches. The journal welcomes clinical research on the pathophysiology, treatment and prevention of osteoporosis and fractures, as well as sarcopenia, disorders of bone and mineral metabolism, and rare or genetically determined bone diseases.
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