Prevalence and Characterization of Somatic Mutations in Chinese Aldosterone-Producing Adenoma Patients

Wang, Qianqian; Li, Xintao; Zhang, Xu; Ma, Xin; Chen, Luyao; Zhang, Yu; Lyu, Xiangjun; Tang, Yuzhe; Huang, Qingbo; Gao, Yu; Yang, Fan; Ouyang, Jinzhi

doi:10.1097/md.0000000000000708

Cited by 53 publications

(33 citation statements)

References 29 publications

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“…ATP, CACNA, CTNNB1 ) is considerably low184345. The current cohort and others from Asia (ranging from 59.5 to 76.8%)1843 reported a higher prevalence of APAs harboring KCNJ5 somatic mutations (52.9% in this cohort).…”

Section: Discussionsupporting

confidence: 43%

The prevalence of CTNNB1 mutations in primary aldosteronism and consequences for clinical outcomes

Wang

Chueh

et al. 2017

Sci Rep

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Constitutive activation of the Wnt pathway/β-catenin signaling may be important in aldosterone-producing adenoma (APA). However, significant gaps remain in our understanding of the prevalence and clinical outcomes after adrenalectomy in APA patients harboring CTNNB1 mutations. The molecular expression of CYP11B2 and gonadal receptors in adenomas were also explored. Adenomas from 219 APA patients (95 men; 44.2%; aged 50.5 ± 11.9 years) showed a high rate of somatic mutations (n = 128, 58.4%). The majority of them harbored KCNJ5 mutations (n = 116, 52.9%); 8 patients (3.7%, 6 women) had CTNNB1 mutations. Patients with APAs harboring CTNNB1 mutations were older and had shorter duration of hypertension. After adrenalectomy, CTNNB1 mutation carriers had a higher possibility (87.5%) of residual hypertension than other APA patients. APAs harboring CTNNB1 mutations have heterogeneous staining of β-catenin and variable expression of gonadal receptors and both CYP11B1 and CYP11B2. This suggests that CTNNB1 mutations may be more related to tumorigenesis rather than excessive aldosterone production.

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Section: Discussionsupporting

confidence: 43%

The prevalence of CTNNB1 mutations in primary aldosteronism and consequences for clinical outcomes

Wang

Chueh

et al. 2017

Sci Rep

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“…Large multicenter studies have confirmed these findings and have shown that these mutations (G151R and L168R) account for 34%-47% of APAs in people of European ancestry (8)(9)(10) and 60%-77% of people of Asian ancestry (11)(12)(13)(14), with differences likely attributable to differences in disease definition. There is also a striking sex dimorphism in European and some Asian cohorts (8,10,11,15,16); European cohorts consistently show that these mutations account for 50%-60% of women with APAs, but only 20% of men, and KCNJ5 mutations are more prevalent in younger patients (8,10).…”

Section: Introductionsupporting

confidence: 53%

Macrolides selectively inhibit mutant KCNJ5 potassium channels that cause aldosterone-producing adenoma

Scholl

Abriola

Zhang

et al. 2017

Journal of Clinical Investigation

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tributed to cell maintenance. LA, UIS, and JSM designed and performed high-throughput screening assays. MP synthesized compounds. CZ and WW performed and analyzed electrophysiology. ENR performed qPCR analysis and ELISAs. UIS and BIK performed Kirby-Bauer disk-diffusion assays. UIS prepared figures and tables. UIS and RPL wrote and edited the main text and supplemental data. UIS, DH, JSM, WW, and RPL oversaw parts of the project or had advisory roles.

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“…One of these (R510X) must result in a truncated non-functional channel. Another APA mutation, V728I, reported previously only once in an APA of a Chinese patient [18,38] is frequently present germline in healthy individuals [39 heterozygous alleles in EXAC database]. This also questions if it alone can account for excessive aldosterone production.…”

Section: Discussionmentioning

confidence: 99%

Gating defects of disease-causing de novo mutations in Ca_v1.3 Ca²⁺ channels

et al. 2018

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Recently, we and others identified somatic and germline de novo gain-of-function mutations in CACNA1D, the gene encoding the α1-subunit of voltage-gated Cav1.3 Ca2+-channels. While somatic mutations identified in aldosterone producing adenomas (APAs) underlie treatment-resistant hypertension, germline CACNA1D mutations are associated with a neurodevelopmental disorder characterized by a wide symptomatic spectrum, including autism spectrum disorder. The number of newly identified CACNA1D missense mutations is constantly growing, but their pathogenic potential is difficult to predict in silico, making functional studies indispensable to assess their contribution to disease risk.Here we report the functional characterization of previously identified CACNA1D APA mutations F747L and M1354I using whole-cell patch-clamp electrophysiology upon recombinant expression in tsA-201 cells. We also investigated if alternative splicing of Cav1.3 affects the aberrant gating of the previously characterized APA mutation R990H and two mutations associated with autism spectrum disorder (A479G and G407R). Splice-variant dependent gating changes are of particular interest for germline mutations, since the relative expression of Cav1.3 splice variants differs across different tissues and within brain regions and might therefore result in tissue-specific phenotypes. Our data revealed a complex gain-of-function phenotype for APA mutation F747L confirming its pathogenic role. Furthermore, we found splice-variant dependent gating changes in R990H, A749G and G407R. M1354I did not change channel function of Cav1.3 splice variants and should therefore be considered a rare non-pathogenic variant until further proof for its pathogenicity is obtained. Our new findings together with previously published data allow classification of pathogenic CACNA1D mutations into four categories based on prototypical functional changes.

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Prevalence and Characterization of Somatic Mutations in Chinese Aldosterone-Producing Adenoma Patients

Abstract: Supplemental Digital Content is available in the text

Cited by 53 publications

References 29 publications

The prevalence of CTNNB1 mutations in primary aldosteronism and consequences for clinical outcomes

The prevalence of CTNNB1 mutations in primary aldosteronism and consequences for clinical outcomes

Macrolides selectively inhibit mutant KCNJ5 potassium channels that cause aldosterone-producing adenoma

Gating defects of disease-causing de novo mutations in Ca_v1.3 Ca²⁺ channels

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Prevalence and Characterization of Somatic Mutations in Chinese Aldosterone-Producing Adenoma Patients

Abstract: Supplemental Digital Content is available in the text

Cited by 53 publications

References 29 publications

The prevalence of CTNNB1 mutations in primary aldosteronism and consequences for clinical outcomes

The prevalence of CTNNB1 mutations in primary aldosteronism and consequences for clinical outcomes

Macrolides selectively inhibit mutant KCNJ5 potassium channels that cause aldosterone-producing adenoma

Gating defects of disease-causing de novo mutations in Cav1.3 Ca2+ channels

Contact Info

Product

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Gating defects of disease-causing de novo mutations in Ca_v1.3 Ca²⁺ channels