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Published on: September 15, 2017
Familial forms and molecular profile of primary hyperaldosteronism
M Araujo-Castro1, P Martín Rojas-Marcos2, P Parra Ramírez2
1Department of Endocrinology and Nutrition Hospital Universitario Ramón y Cajal, Madrid, Spain.
Insights
Primary hyperaldosteronism (PAH), a common cause of secondary hypertension, has both hereditary and sporadic forms. This review details familial PAH types and the genetic mutations found in sporadic PAH cases.
Area of Science:
- Endocrinology
- Genetics
- Cardiovascular Medicine
Background:
- Primary hyperaldosteronism (PAH) is the leading cause of secondary arterial hypertension.
- While most PAH cases are sporadic, 5% have a hereditary basis (familial PAH).
- Understanding the genetic underpinnings of PAH is crucial for diagnosis and treatment.
Purpose of the Study:
- To review the distinct forms of familial primary hyperaldosteronism.
- To describe the molecular genetic profile of patients with sporadic PAH.
- To consolidate current knowledge on the genetic etiology of PAH.
Main Methods:
- Literature review of familial and sporadic primary hyperaldosteronism.
- Analysis of genetic mutations associated with different PAH subtypes.
- Synthesis of information on gene fusions and germline/somatic mutations.
Main Results:
- Four types of familial PAH are described, linked to specific gene alterations (CYP11B2/CYP11B1 fusion, CLCN2, KCNJ5, CACNA1H mutations).
- Somatic mutations, particularly in KCNJ5, ATP1A1, ATP2B3, and CACNA1D, are identified in 50% of sporadic PAH cases.
- Different genetic mechanisms underlie familial and sporadic forms of PAH.
Conclusions:
- Familial PAH arises from distinct genetic mutations affecting aldosterone synthesis regulation.
- Sporadic PAH frequently involves somatic mutations in key ion channel and transporter genes.
- Comprehensive genetic analysis is essential for classifying and managing PAH patients.
Abstract:
Primary hyperaldosteronism (PAH) is the most frequent cause of secondary arterial hypertension. Most PAHs occur sporadically, but 5% of cases have a hereditary origin (familial PAH). Four forms of familial PAH have been described. Type I familial PAH is produced by a fusion of the CYP11B2 and CYP11B1 genes, in this way the synthesis of aldosterone becomes to be regulated by ACTH instead of by angiotensin II. In type II, III and IV familial PAH there is an increase in the transcription and expression of CYP11B2 responsible for aldosterone synthesis due to a germinal mutation in CLCN2, KCNJ5 and CACNA1H, respectively. On the other hand, somatic mutations have been identified in 50% of sporadic PAHs, with gain-of-function mutations at the level of KCNJ5, ATP1A1, ATP2B3 and CACNA1D being the most common. This review provides a detailed description of the different forms of familial PAH and the molecular profile of patients with sporadic PAH.
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