Timeline of Advances in Genetics of Primary Aldosteronism

Meyer, Lucie S.; Reincke, Martin; Williams, Tracy Ann

doi:10.1007/978-3-030-25905-1_11

Lucie S. Meyer³,
Martin Reincke³ &
Tracy Ann Williams^3,4

Part of the book series: Experientia Supplementum ((EXS,volume 111))

1766 Accesses

Abstract

The overwhelming majority of cases of primary aldosteronism (PA) occur sporadically due to a unilateral aldosterone-producing adenoma (APA) or bilateral idiopathic adrenal hyperplasia. Familial forms of PA are rare with four subtypes defined to date (familial hyperaldosteronism types I–IV). The molecular basis of familial hyperaldosteronism type I (FH type I or glucocorticoid-remediable aldosteronism) was established in 1992; two decades later the genetic variant causing FH type III was identified and germline mutations causing FH type IV and FH type II were determined soon after. Effective diagnostic protocols and methods to detect the overactive gland in unilateral PA by adrenal venous sampling followed by laparoscopic adrenalectomy have made available APAs for scientific studies. In rapid succession, following the widespread use of next-generation sequencing, recurrent somatic driver mutations in APAs were identified in genes encoding ion channels and transporters. The development of highly specific monoclonal antibodies against key enzymes in adrenal steroidogenesis has unveiled the heterogeneous features of the diseased adrenal in PA and helped reveal the high proportion of APAs with driver mutations. We discuss what is known about the genetics of PA that has led to a clearer understanding of the disease pathophysiology.

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Abbreviations

ACTH:: Adrenocorticotropic hormone
APA:: Aldosterone-producing adenoma
APCC:: Aldosterone-producing cell cluster
ARR:: Aldosterone-to-renin ratio
ATP:: Adenosine triphosphate
AVS:: Adrenal venous sampling
BAH:: Bilateral adrenal hyperplasia
Ca_v1.3:: Calcium voltage-gated channel subunit alpha 1D
Ca_v3.2:: Calcium voltage-gated channel subunit alpha 1H
ClC-2:: Chloride channel protein 2
ENS@T:: European Network for the Study of Adrenal Tumours
FH:: Familial hyperaldosteronism
GIRK1-4:: G protein-activated inwardly rectifying potassium channel 1-4
GRA:: Glucocorticoid-remediable aldosteronism
HAC15 cell:: Human adrenocortical cells
HEK cells:: Human embryonic kidney cells
MRA:: Mineralocorticoid receptor antagonists
NCI H295R cell line:: Human adrenocortical cell line
NGS:: Next-generation sequencing
PA:: Primary aldosteronism
pAATLs:: Potential APCC-to-APA-transitional lesions
PASNA:: Primary aldosteronism with seizures and neurologic abnormalities
PMCA:: Plasma membrane Ca²⁺-ATPase
SFRP2:: Secreted frizzled related protein 2
SSCP:: Single-strand conformation polymorphism
TASK1:: Potassium two-pore domain channel subfamily K member 3
TM:: Transmembrane
zF:: Zona fasciculata
zG:: Zona glomerulosa
zR:: Zona reticularis

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Acknowledgments

The work of M. Reincke is supported by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No [694913]). M Reincke and TA Williams are supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) Projektnummer: 314061271 – TRR 205. M. Reincke is additionally supported by DFG grant RE 752/20-1 and by the Else Kröner-Fresenius Stiftung in support of the German Conns Registry-Else-Kröner Hyperaldosteronism Registry (2013_A182 and 2015_A171).

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Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany
Lucie S. Meyer, Martin Reincke & Tracy Ann Williams
Division of Internal Medicine and Hypertension, Department of Medical Sciences, University of Turin, Turin, Italy
Tracy Ann Williams

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Lucie S. Meyer
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Martin Reincke
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2nd Department of Internal Medicine, Faculty of Medicine, Semmelweis University, MTA-SE Molecular Medicine Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary
Peter Igaz
Department of Laboratory Medicine, Faculty of Medicine, Semmelweis University, “Lendület” Hereditary Endocrine Tumors Research Group, Hungarian Academy of Sciences and Semmelweis University, Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary
Attila Patócs

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Meyer, L.S., Reincke, M., Williams, T.A. (2019). Timeline of Advances in Genetics of Primary Aldosteronism. In: Igaz, P., Patócs, A. (eds) Genetics of Endocrine Diseases and Syndromes. Experientia Supplementum, vol 111. Springer, Cham. https://doi.org/10.1007/978-3-030-25905-1_11

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DOI: https://doi.org/10.1007/978-3-030-25905-1_11
Published: 07 October 2019
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