Genomic and sequence variants of protein kinase A regulatory subunit type 1β (PRKAR1B) in patients with adrenocortical disease and Cushing syndrome.,Genetics in Medicine

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Genomic and sequence variants of protein kinase A regulatory subunit type 1β (PRKAR1B) in patients with adrenocortical disease and Cushing syndrome.
Genetics in Medicine ( IF 6.6 ) Pub Date : 2020-09-08 , DOI: 10.1038/s41436-020-00958-1
Ludivine Drougat ₁ , Nikolaos Settas ₁ , Cristina L Ronchi _{2,

3} , Kerstin Bathon ₄ , Davide Calebiro _{2,

4,

5} , Andrea Gutierrez Maria ₁ , Sara Haydar ₁ , Antonios Voutetakis ₁ , Edra London ₁ , Fabio R Faucz ₁ , Constantine A Stratakis ₁

Affiliation

Purpose

Protein kinase A (PKA) subunit defects (in PRKAR1A and PRKACA) are known to contribute to adrenal tumor pathogenesis. We studied the PRKAR1B gene for any genetic changes in bilateral adrenocortical hyperplasia (BAH) and cortisol-producing adrenal adenomas (CPA).

Methods

Exome sequencing and PRKAR1B copy-number variant (CNV) analysis were performed in 74 patients with BAH and 21 with CPA. PKA activity was studied in tumors with defects; sequence variants were investigated in vitro.

Results

Three PRKAR1B germline variants (p.I40V, p.A67V, p.A300T) were identified among 74 patients with BAH. PRKAR1B copy-number gains (CNG) were found in 3 of 21 CPAs, one in a tumor carrying a somatic PRKACA “hotspot” pathogenic variant p.L206R. CPAs bearing PRKAR1B CNGs showed higher PRKAR1B messenger RNA (mRNA) levels and reduced PKA activity. Baseline PKA activity was also decreased for p.A67V and p.A300T in vitro, and mutant PRKAR1β bound PRKACα in fluorescence resonance energy transfer (FRET) recordings of cotransfected HEK293 cells stronger than normal.

Conclusion

PRKAR1B is yet another PKA subunit that may potentially contribute to adrenal tumor formation. Its involvement in adrenocortical disease may be different from that of other subunits, because PRKAR1B variants and PRKAR1B CNGs were associated with decreased (rather than increased) overall PKA activity in vitro.

中文翻译：

肾上腺皮质疾病和库欣综合征患者中蛋白激酶 A 调节亚基 1β 型 (PRKAR1B) 的基因组和序列变体。

目的

已知蛋白激酶 A (PKA) 亚基缺陷（在 PRKAR1A 和 PRKACA 中）有助于肾上腺肿瘤的发病机制。我们研究了PRKAR1B基因在双侧肾上腺皮质增生 (BAH) 和产生皮质醇的肾上腺腺瘤 (CPA) 中的任何遗传变化。

方法

在 74 名 BAH 患者和 21 名 CPA 患者中进行了外显子组测序和PRKAR1B拷贝数变异 (CNV) 分析。在有缺陷的肿瘤中研究了 PKA 活性；在体外研究了序列变体。

结果

在 74 名 BAH 患者中鉴定出三种PRKAR1B种系变异体（p.I40V、p.A67V、p.A300T）。在 21 名 CPA 中的 3 名中发现了PRKAR1B拷贝数增加 (CNG)，其中一名在携带体细胞PRKACA “热点”致病性变异 p.L206R 的肿瘤中。携带PRKAR1B CNGs的 CPA表现出更高的PRKAR1B信使 RNA (mRNA) 水平和降低的 PKA 活性。p.A67V 和 p.A300T 在体外的基线 PKA 活性也降低，并且突变 PRKAR1β 在共转染的 HEK293 细胞的荧光共振能量转移 (FRET) 记录中结合 PRKACα 比正常情况强。