A Novel GNAS Duplication Associated With Loss-of-Methylation Restricted to Exon A/B Causes Pseudohypoparathyroidism Type Ib (PHP1B).
A Novel GNAS Duplication Associated With Loss-of-Methylation Restricted to Exon A/B Causes Pseudohypoparathyroidism Type Ib (PHP1B).
复制标题
一种新的GNAS重复与限制于外显子A/B的甲基化缺失相关导致Ib型假性甲状旁腺功能减退症（PHP 1 B）
DOI：
10.1002/jbmr.4209
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Jüppner H
中科院分区：
文献类型：
--
作者：
Reyes M;Kagami M;Kawashima S;Pallotta J;Schnabel D;Fukami M;Jüppner H
Ib型假性甲状旁腺功能减退症（PHP 1B）的特征是对甲状旁腺激素（PTH）的抵抗，导致低钙血症和高磷血症，在某些情况下对其他激素的抵抗。受这种疾病影响的患者在差异甲基化的GNAS外显子A/B处均存在甲基化缺失（LOM），这降低了来自母体等位基因的刺激性G蛋白α亚基（Gsα）的表达。这导致在近端肾小管中，其中父本GNAS等位基因对该信号蛋白的表达贡献不大，从而导致很少或没有Gsα表达，从而引起PTH抗性。我们现在描述一个PHP 1 B患者，其基因组从头GNAS重复约88 kb，这与仅限于外显子A/B的LOM有关。多重连接依赖性探针扩增（MLPA），比较基因组杂交（CGH），和全基因组测序（WGS）确定重复的DNA片段从GNAS外显子AS 1（端粒断裂点）延伸到两个不完美重复之间的一个小区域，就在LOC 105372695（着丝粒断裂点）的上游。我们的新的重复比以前描述的染色体20 q13部分的重复/三重复要短得多，并且它不影响外显子AS和XL的甲基化。基于这些和先前的发现，似乎合理的是，所鉴定的基因组异常顺式破坏了建立或维持外显子A/B甲基化所需的转录物的作用。我们的研究结果扩展了PHP 1B的分子原因，并为维持母体Gsα表达和预防PTH耐药性所需的结构GNAS特征提供了额外的见解。
Pseudohypoparathyroidism type Ib (PHP1B) is characterized by resistance to parathyroid hormone (PTH) leading to hypocalcemia and hyperphosphatemia, and in some cases resistance toward additional hormones. Patients affected by this disorder all share a loss-of-methylation (LOM) at the differentially methylated GNAS exon A/B, which reduces expression of the stimulatory G protein α-subunit (Gsα) from the maternal allele. This leads in the proximal renal tubules, where the paternal GNAS allele does not contribute much to expression of this signaling protein, to little or no Gsα expression thereby causing PTH resistance. We now describe a PHP1B patient with a de novo genomic GNAS duplication of approximately 88 kb, which is associated with LOM restricted to exon A/B alone. Multiplex ligation-dependent probe amplification (MLPA), comparative genomic hybridization (CGH), and whole-genome sequencing (WGS) established that the duplicated DNA fragment extends from GNAS exon AS1 (telomeric breakpoint) to a small region between two imperfect repeats just upstream of LOC105372695 (centromeric breakpoint). Our novel duplication is considerably shorter than previously described duplications/triplications in that portion of chromosome 20q13 and it does not affect methylation at exons AS and XL. Based on these and previous findings, it appears plausible that the identified genomic abnormality disrupts in cis the actions of a transcript that is required for establishing or maintaining exon A/B methylation. Our findings extend the molecular causes of PHP1B and provide additional insights into structural GNAS features that are required for maintaining maternal Gsα expression and for preventing PTH-resistance.
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DOI：
10.1073/pnas.0408268102
发表时间：
2005-05-17
影响因子：
11.1
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影响因子：
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作者：
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