Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism

Scholl, Ute I.; Stölting, Gabriel; Nelson‐Williams, Carol; Vichot, Alfred A.; Choi, Murim; Loring, Erin; Prasad, Manju L.; Goh, Gerald; Carling, Tobias; Juhlin, C. Christofer; Quack, Ivo; Rump, Lars Christian; Thiel, Anne; Lande, Marc B.; Frazier, Britney G; Rasoulpour, Majid; Bowlin, David L; Sethna, Christine B.; Trachtman, Howard; Fahlke, Christoph; Lifton, Richard P.

doi:10.7554/elife.06315

Cited by 301 publications

(291 citation statements)

References 57 publications

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“…In the germline compartment, rare instances of mutations were also identified for KCNJ5, CACNA1D and CACNA1H, mainly in families with primary aldosteronism, and as de novo mutations (5,9,10).…”

Section: Methodsmentioning

confidence: 99%

ENDOCRINE TUMOURS: The genomics of adrenocortical tumors

Faillot

Assié

2016

European Journal of Endocrinology

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The last decade witnessed the emergence of genomics, a set of high-throughput molecular measurements in biological samples. These pan-genomic and agnostic approaches have revolutionized the molecular biology and genetics of malignant and benign tumors. These techniques have been applied successfully to adrenocortical tumors. Exome sequencing identified new major drivers in all tumor types, including KCNJ5, ATP1A1, ATP2B3 and CACNA1D mutations in aldosterone-producing adenomas (APA), PRKACA mutations in cortisol-producing adenomas (CPA), ARMC5 mutations in primary bilateral macronodular adrenocortical hyperplasia (PBMAH) and ZNRF3 mutations in adrenocortical carcinomas (ACC). Moreover, the various genomic approaches -including exome sequencing, transcriptome, miRNome, genome and methylome -converge into a single molecular classification of adrenocortical tumors. Especially for ACC, two main molecular groups have emerged, showing major differences in outcomes. These ACC groups differ by their gene expression profiles, but also by recurrent mutations and specific DNA hypermethylation patterns in the subgroup of poor outcome. The clinical impact of these findings is just starting. The main altered signaling pathways now become therapeutic targets. The molecular groups of diseases individualize robust subtypes within diseases such as APA, CPA, PBMAH and ACC. A revised nosology of adrenocortical tumors should impact the clinical research. Obvious consequences also include genetic counseling for the new genetic diseases such as ARMC5 mutations in PBMAH, and a better prognostication of ACC based on targeted measurements of a few discriminant molecular alterations. Identifying the main molecular groups of adrenocortical tumors by extensively gathering the molecular variations is a significant step forward towards precision medicine.

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Section: Methodsmentioning

confidence: 99%

ENDOCRINE TUMOURS: The genomics of adrenocortical tumors

Faillot

Assié

2016

European Journal of Endocrinology

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“…Scholl and coworkers identified mutations in CACNA1H by exome sequencing of samples from 40 unrelated early-onset cases of hypertension (Scholl et al 2015b). One hot spot mutation was identified at p.M1549V in the CACNA1H gene in five cases (Table 5).…”

Section: Cacna1hmentioning

confidence: 99%

“…Azizan et al 2012a, Azizan et al 2013, Beuschlein et al 2013, Dutta et al 2014, Zilbermint et al 2015, Scholl et al 2015b. APAs may occur in patients of all ages, but a high prevalence is seen in patients 40-50 years of age.…”

Section: :10mentioning

confidence: 99%

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Genetics of primary hyperaldosteronism

Dutta

Söderkvist

Gimm

2016

Endocrine-Related Cancer

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Hypertension is a common medical condition and affects approximately 20% of the population in developed countries. Primary aldosteronism is the most common form of secondary hypertension and affects 8-13% of patients with hypertension. The two most common causes of primary aldosteronism are aldosterone-producing adenoma and bilateral adrenal hyperplasia. Familial hyperaldosteronism types I, II and III are the known genetic syndromes, in which both adrenal glands produce excessive amounts of aldosterone. However, only a minority of patients with primary aldosteronism have one of these syndromes. Several novel susceptibility genes have been found to be mutated in aldosterone-producing adenomas: KCNJ5, ATP1A1, ATP2B3, CTNNB1, CACNA1D, CACNA1H and ARMC5. This review describes the genes currently known to be responsible for primary aldosteronism, discusses the origin of aldosterone-producing adenomas and considers the future clinical implications based on these novel insights.

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“…12 A clear familial form of PA has just been described that is caused by a heterozygous mutation in CACNA1H that encodes the voltage-gated calcium channel Cav3.2. 13 The Cav3.2 M1549V mutation results in a dramatic impairment of channel inactivation and activation at more hyperpolarized potentials resulting in an increase in intracellular Ca 2+ concentrations.…”

Section: Familial Hyperaldosteronismmentioning

confidence: 99%