A novel deletion involving the first GNAS exon encoding Gsα causes PHP1A without methylation changes at exon A/B.
A novel deletion involving the first GNAS exon encoding Gsα causes PHP1A without methylation changes at exon A/B.
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DOI：
10.1016/j.bone.2022.116344
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发表时间：
2022-04
期刊：
影响因子：
4.1
通讯作者：
Juppner, Harald
中科院分区：
文献类型：
--
作者：
Campbell, Devon;Reyes, Monica;Kaygusuz, Sare Betul;Abali, Saygin;Guran, Tulay;Bereket, Abdullah;Kagami, Masayo;Turan, Serap;Juppner, Harald
关键词：
受假性甲状旁腺功能减退症1A型（PHP 1A）影响的个体显示高磷酸盐血症和低钙血症，尽管PTH水平升高，以及奥尔布赖特遗传性骨营养不良（AHO）的特征。PHP 1A由涉及编码刺激性G蛋白α亚基（Gsα）的母体GNAS外显子1-13的变体引起。MLPA和aCGH分析导致在男性PHP 1A患者中鉴定出涉及GNAS外显子1的从头1284-bp缺失。该新变体与先前在另一名PHP 1A患者（参考文献Li et al.（2020），患者2）中鉴定的1438-bp缺失重叠，该缺失从外显子1启动子延伸到上游内含子区。后一种缺失与GNAS外显子A/B的甲基化降低相关，即在大多数假性甲状旁腺功能减退症1型B（PHP 1 B）患者中去甲基化的差异甲基化区域（DMR）。相比之下，我们的患者的基因组DNA显示没有证据表明表观遗传GNAS缺陷，如通过MS-MLPA和焦磷酸测序所确定的。因此，这些发现减少了该区域，除了外显子A/B端粒的其他核苷酸序列外，该区域可能经历组蛋白修饰或与转录因子相互作用，并且可能与在该位点建立母体甲基化印记所需的未知蛋白质相互作用。总之，外显子A/B端粒区约1300 bp内的核苷酸缺失或变化可能是导致PHP 1 B变体在外显子A/B DMR处完全或不完全甲基化缺失的原因。此外，当调查疑似PHP 1A患者时，应考虑MLPA，以在这个难以分析的包含GNAS外显子1的基因组区域内搜索结构异常。
Individuals affected by pseudohypoparathyroidism type 1A (PHP1A) display hyperphosphatemia and hypocalcemia despite elevated PTH levels, as well as features of Albright Hereditary Osteodystrophy (AHO). PHP1A is caused by variants involving the maternal GNAS exons 1–13 encoding the stimulatory G protein α-subunit (Gsα). MLPA and aCGH analysis led in a male PHP1A patient to identification of a de novo 1284-bp deletion involving GNAS exon 1. This novel variant overlaps with a previously identified 1438-bp deletion in another PHP1A patient (ref. Li et al. (2020), patient 2) that extends from the exon 1 promoter into the up-stream intronic region. This latter deletion is associated with reduced methylation at GNAS exon A/B, i.e. the differentially methylated region (DMR) that is demethylated in most pseudohypoparathyroidism type 1B (PHP1B) patients. In contrast, genomic DNA from our patient revealed no evidence for an epigenetic GNAS defect as determined by MS-MLPA and pyrosequencing. These findings thus reduce the region, which, in addition to other nucleotide sequences telomeric of exon A/B, may undergo histone modifications or interacts with transcription factors and possibly as-yet unknown proteins that are required for establishing the maternal methylation imprints at this site. Taken together, nucleotide deletions or changes within an approximately 1300-bp region telomeric of exon A/B could be a cause of PHP1B variants with complete or incomplete loss-of-methylation at the exon A/B DMR. In addition, when investigating patients with suspected PHP1A, MLPA should be considered to search for structural abnormalities within this difficult to analyze genomic region comprising GNAS exon 1.
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影响因子：
15.9
作者：
CHASE, LR;MELSON, GL;AURBACH, GD
通讯作者：
AURBACH, GD
DOI：
10.1002/jbmr.4209
发表时间：
2021-03
期刊：
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
影响因子：
--
作者：
Reyes M;Kagami M;Kawashima S;Pallotta J;Schnabel D;Fukami M;Jüppner H
通讯作者：
Jüppner H
影响因子：
5.8
作者：
Danzig, Jennifer;Li, Dong;Levine, Michael A.
通讯作者：
Levine, Michael A.
影响因子：
5.8
作者：
Elli, Francesca M.;de Sanctis, Luisa;Mantovani, Giovanna
通讯作者：
Mantovani, Giovanna
影响因子：
158.5
作者：
FARFEL, Z;BRICKMAN, AS;BOURNE, HR
通讯作者：
BOURNE, HR