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

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

机构信息

Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA.

Institute of Metabolism and System Research (IMSR), University of Birmingham, Birmingham, United Kingdom.

出版信息

Genet Med. 2021 Jan;23(1):174-182. doi: 10.1038/s41436-020-00958-1. Epub 2020 Sep 8.

DOI:10.1038/s41436-020-00958-1
PMID:32895490
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7796991/
Abstract

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.

摘要

目的

蛋白激酶 A（PKA）亚基缺陷（PRKAR1A 和 PRKACA 中）已知会导致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

对 74 例 BAH 患者和 21 例 CPA 患者进行了外显子组测序和 PRKAR1B 拷贝数变异（CNV）分析。在存在缺陷的肿瘤中研究了 PKA 活性；在体外研究了序列变异。

结果

在 74 例 BAH 患者中发现了 3 种 PRKAR1B 种系变异（p.I40V、p.A67V、p.A300T）。在 21 例 CPAs 中发现了 3 例 PRKAR1B 拷贝数增加（CNG），其中 1 例肿瘤携带体细胞 PRKACA“热点”致病性变异 p.L206R。携带 PRKAR1B CNG 的 CPAs 表现出更高的 PRKAR1B 信使 RNA（mRNA）水平和降低的 PKA 活性。体外，p.A67V 和 p.A300T 的基础 PKA 活性也降低，突变的 PRKAR1β 在共转染的 HEK293 细胞的荧光共振能量转移（FRET）记录中比正常 PRKACα 结合更强。

结论

PRKAR1B 是另一个可能有助于肾上腺肿瘤形成的 PKA 亚基。它在肾上腺皮质疾病中的作用可能与其他亚基不同，因为 PRKAR1B 变体和 PRKAR1B CNG 与体外总体 PKA 活性降低（而非增加）相关。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4652/7796991/91940d001d97/nihms-1630825-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4652/7796991/a959993ec918/nihms-1630825-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4652/7796991/24d78acb9867/nihms-1630825-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4652/7796991/91940d001d97/nihms-1630825-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4652/7796991/a959993ec918/nihms-1630825-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4652/7796991/24d78acb9867/nihms-1630825-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4652/7796991/91940d001d97/nihms-1630825-f0003.jpg

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