Saga of Familial Hyperaldosteronism
2018; Lippincott Williams & Wilkins; Volume: 71; Issue: 6 Linguagem: Inglês
10.1161/hypertensionaha.118.11150
ISSN1524-4563
AutoresLivia Lenzini, Selene Prisco, Brasilina Caroccia, Gian Paolo Rossi,
Tópico(s)Cardiovascular, Neuropeptides, and Oxidative Stress Research
ResumoHomeHypertensionVol. 71, No. 6Saga of Familial Hyperaldosteronism Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBSaga of Familial HyperaldosteronismYet a New Channel Livia Lenzini, Selene Prisco, Brasilina Caroccia and Gian Paolo Rossi Livia LenziniLivia Lenzini From the Department of Medicine, University of Padova, Italy. , Selene PriscoSelene Prisco From the Department of Medicine, University of Padova, Italy. , Brasilina CarocciaBrasilina Caroccia From the Department of Medicine, University of Padova, Italy. and Gian Paolo RossiGian Paolo Rossi From the Department of Medicine, University of Padova, Italy. Originally published7 May 2018https://doi.org/10.1161/HYPERTENSIONAHA.118.11150Hypertension. 2018;71:1010–1014Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2018: Previous Version 1 In 1953, Litynski1 reported in a Polish journal the first case of an adrenocortical adenoma associated with hypertension and hypokalemia that was cured by adrenalectomy. Three years later, Conn2 reported a similar case and described the full characterization of the syndrome of primary aldosteronism (PA). Compelling evidence is now established that PA, albeit deceiving diagnosis in the majority of the cases because of the lack of hypokalemia, is the most common endocrine cause of hypertension. Moreover, if adrenal vein sampling is systematically used, PA is surgically curable in about two thirds of the cases.3,4 Exceptions to this rule entail the familial cases of PA because of germline mutations that, by definition, involve both adrenals and, therefore, cannot be cured by unilateral adrenalectomy. The familial occurrence of PA has been known for decades since the discovery of PA in 1966 by Sutherland et al.5 Of note, they reported that in some pedigrees of patients with PA, the syndrome could be corrected by glucocorticoids, which led them to define this condition glucocorticoid-remediable aldosteronism5—a condition today redefined as familial hyperaldosteronism (FH) type 1 (FH-1). The molecular mechanisms of FH-1 remained unknown until 1992 when a chimeric gene deriving from unequal crossing over of the CYP11B1 and CYP11B2 genes was identified as the culprit of FH-1.6 Genetic testing for this form based on long polymerase chain reaction7 rapidly followed, which allowed the identification of familial cases of PA without the chimeric gene that by default were provisionally classified as FH type 2. A long quest for responsible genes was unsuccessful8 until a few months ago. Moreover, an impressive amount of research work in the past 6 years has allowed the discovery of additional germline mutations in multiple genes and to a new classification of FH (Table). Familial forms of PA with germline mutations account now from 1% to 5% of PA cases, depending on the cohorts studied, and are transmitted as an autosomal dominant trait. Therefore, the purpose of this review is to provide an update on FH taking account of the recent discoveries, their genetic basis, and their mechanistic implications.Table 1. Clinical and Molecular Classification of FHTypeSubtypePrevalence, %*Cytogenetic LocationGene MutationCT FindingsTreatmentDrug-Resistant HypertensionClinical FeaturesFH-10.5–18q24CYP11B2/CYP11B1 ChimericBAH or APALow-dose dexamethasoneYes (with drugs other than dexamethasone)Early-onset PA, hybrid steroids, cerebrovascular eventsFH-253q27CLCN2 (R172Q, M22K, G24D, S865R, Y26N)BAH or APA or no adrenal abnormalitiesMRANoEarly-onset PAFH-3Type A0.311q23KCNJ5 (T158A, I157S, E145Q)BAHBilateral adrenalectomyYesSevere early-onset PAType B0.311q23KCNJ5 (G151E, Y152C)NoMRANoMild PAFH-4NA16p13CACNA1H (M1549V, S196L, P2083L, V1951E)Little or no adrenal abnormalitiesMRANoEarly-onset PA, mental retardation, social and development disordersFH-5 (PASNA)NA3p14.3CACNA1D (I770M, G403D)No adrenal abnormalitiesCalcium channel blockersNoEarly-onset PA, seizures, neurological abnormalitiesAPA indicates aldosterone-producing adenoma; BAH, bilateral adrenal hyperplasia; CT, computed tomography; FH, familial hyperaldosteronism; MRA, mineralocorticoid receptor antagonist; NA, not available; PA, primary aldosteronism; and PASNA, primary aldosteronism with seizures and neurologic abnormalities.*In patients with PA.FH Type 1As mentioned, the first familial forms of PA reported in the 60s were defined glucocorticoid-remediable aldosteronism (OMIM [Online Mendelian Inheritance in Man]: 103900) because they were found to be corrected by low-dose dexamethasone treatment.5,9 More recently, they were renamed as FH-1, after the discovery of other familial forms. FH-1, inherited as an autosomal dominant disorder, is present in ≤1% of familial cases among patients with PA and has phenotypic heterogeneity (Table). In fact, although hypertension is often of early onset and may be sufficient to result in early death, commonly because of intracerebral hemorrhage, it has been reported that the degree of hypertension varies widely even within the same family. Moreover, the severity of hypertension correlates with the sex: female subjects show a less-severe phenotype and a better prognosis.10 Its molecular basis was clarified in 1992 when Lifton et al6 identified a fusion of the promoter sequence of the CYP11B1 gene with the coding region of the CYP11B2 gene in an affected pedigree. This chimeric structure of the gene is held to originate from an unequal crossing over of the CYP11B1 and CYP11B2 genes, two 95% homologous genes located on chromosome 8q24. The regulatory region of the chimeric gene is altered in that the CYP11B1 promoter ends upstream of the CYP11B2 coding sequences, which explains why the latter gene becomes responsive to adrenocorticotropic hormone. The resulting phenotype features ectopic expression of aldosterone synthase encoded by CYP11B2 in the adrenal zona fasciculata under the control of adrenocorticotropic hormone instead of angiotensin II (Figure 1A). Moreover, the chimeric enzyme catalyses the C-18 hydroxylation and C-18 oxidation of cortisol made by the zona fasciculata, thus causing the production of the hybrid steroids 18OH-cortisol and 18-oxo cortisol.6 This also explains why in affected individuals specific treatment with low-dose dexamethasone usually normalizes blood pressure and corrects completely the hyperaldosteronism—a clear-cut example of molecularly targeted precision medicine.Download figureDownload PowerPointFigure 1. Genetic causes of familial aldosteronism (FH). A, FH-1 is because of the fusion of the promoter sequence of the CYP11B1 gene with the coding region of the CYP11B2. The regulatory region of the resulting chimeric gene is altered, and the CYP11B2 gene becomes responsive to the adrenocorticotropic hormone (ACTH). This translates in an ectopic expression of aldosterone synthase in the adrenal zona fasciculata under the control of ACTH. No data exist about alterations of the activity of ion channels in this disease. B, Germline gain-of-function mutations were identified in cases with FH-2 in the gene CLCN2 coding for the CIC-2 chloride channel. These cause enhanced chloride efflux, membrane depolarization, increased CYP11B2 expression, and aldosterone overproduction. C, In FH-3 cases, the disease occurs as a result of Kir3.4 (KCNJ5) mutations, which cause a loss of selectivity for K+, Na+ influx, depolarization of the cell, with ensuing entry of Ca2+ via voltage-gated T-type Ca2+ channels and autonomous production of aldosterone. D, Two additional genetic causes of FH are mutations in CACNA1H (FH-4) and CACNA1D (primary aldosteronism with seizures and neurologic abnormalities [PASNA]) genes coding for the T-type Cav3.2 and L-type Cav1.3 voltage-gated calcium channels, respectively. These mutations activate channels at less-depolarized potentials with ensuing increased Ca2+ influx.A genetic test based on long polymerase chain reaction soon followed the discovery of the chimeric gene,11 thus allowing a conclusive diagnosis of FH-1. It was thereafter ascertained that FH-1 is a rare disease with a prevalence <1% in PA.12FH Type 2Familial cases of PA that do not respond to glucocorticoid treatment were known for years, but only the availability of the genetic test for FH-1 allowed the determination that they did not have the chimeric gene. These cases were, therefore, by exclusion defined as FH type 2 (OMIM: 605635). They have a prevalence of 5% in PA cases and comprise either adrenocortical hyperplasia or aldosterone-producing adenoma (APA) and are clinically indistinguishable from sporadic PA except than for the familial occurrence.13,14Of note, although by linkage analysis a quantitative trait locus was identified on chromosome 7p22,8 the responsible gene(s) remain unknown until recently when Lifton et al starting from a multiplex kindred featuring autosomal dominant FH type 2 originally reported by Stowasser et al14 in 1992, identified a recurrent functional variant (R172Q) in the CLCN2 gene in 8 of the probands with early-onset PA (Table). This gene encodes the ClC-2 (chloride channel), which is expressed in many tissues, including brain, kidney, lung, intestine, and the adrenal gland. Using exome sequencing in 80 additional probands with unsolved early-onset PA, the authors identified 2 de novo mutations (M22K and R172Q) and 4 independent occurrences of the R172Q (Figure 2).15 In some of the probands carrying the mutations, the phenotype ameliorated with age, suggesting an incomplete penetrance. When tested in vitro in zona glomerulosa cells (H295R), these germline mutations showed gain of function, for example, enhanced chloride efflux at physiological membrane potentials, as compared with wild-type channels and, therefore, caused membrane depolarization, increased CYP11B2 expression, and aldosterone overproduction (Figure 1B).Download figureDownload PowerPointFigure 2. Gain-of-function variants in the CIC-2 chloride channel identified in patients with early-onset primary aldosteronism. Stars indicate variant positions in the N terminus, D helix, K helix, and C terminus. Intracellular loop of CIC-2 is shown in black. CSB1 and CSB2 are cystathionine-β-synthase domains that can affect gating of CIC channels, here shown with white ellipses.In the same journal issue, by analyzing 12 patients with young-onset hypertension and hyperaldosteronism diagnosed by 25 years of age, Zennaro et al16 reported an additional de novo germline CLCN2 variant (G24D) in a highly conserved inactivation site of the N-terminal cytoplasmic domain (Figure 2). They explored the impact of the G24D variant on the membrane potential of H295R cells transfected with this mutation under basal and Ang II- and K+-stimulated conditions. According to their findings, the mutation conferred higher aldosterone production under all conditions. Moreover, they could demonstrate that whereas in wild-type H295R, aldosterone synthesis depended only on T-type calcium channel activity, in mutated cells, it involved both L-type and T-type calcium channel activity.16 Thus, CLCN2 variants result in a strong gain of function, in line with the dominant clinical phenotype caused by the mutations even if present only in the heterozygous state.Noteworthy, the identification of these chloride channel mutations pointed for the first time to a role of anion channels in the regulation of cell membrane potential and aldosterone biosynthesis in adrenal zona glomerulosa. Thus, these seminal discoveries will likely generate new possibilities for the diagnosis and, possibly, treatment of early-onset PA cases.FH Type 3In 2011, alongside the identification of somatic mutations in APA in the KCNJ5 gene encoding the Kir3.4 K+ channel (OMIM: 600734), new forms of FH were discovered17 and defined as FH type 3 (FH-3). A novel clinical molecular classification was then proposed,18 which defines FH-3 as a genetic disease made of 2 distinct subtypes: 1 severe (type A) requiring bilateral laparoscopic adrenalectomy and 1 milder (type B) usually responding well to antihypertensive therapy (Table). The prevalence of these forms is low, and it was reported to be ≈0.3% of all patients with PA.19FH-3 Type AChoi et al17 examined a pedigree characterized by severe aldosteronism and massive bilateral adrenal hyperplasia, which required bilateral adrenalectomy because of drug-resistant hypertension. The index case and his 2 daughters had a mutation (T158A) in the KCNJ5 gene, mapping near to the Kir3.4 selectivity filter. The mutation causes a threonine-to-alanine substitution at codon 158 resulting in reduced K+ selectivity, increased Na+ conductance, and cell membrane depolarization (Figure 1C).Another heterozygous mutation at position 470, resulting in isoleucine-to-serine substitution at amino acid 157 (I157S), was thereafter found in a mother and daughter, who presented with severe PA, bilateral massive adrenal hyperplasia, and early-onset hypertension refractory to drug treatment.20A further E145Q germline mutation previously known to occur in APA was reported in a white girl presenting at the age of 2 years with polydipsia, polyuria, and failure to thrive.21,22 She was found to have profound hypokalemia, severe hyperaldosteronism with renin suppression, and arterial hypertension resistant to treatment, which led to bilateral laparoscopic adrenalectomy in spite of negative computed tomography and magnetic resonance imaging. Like for other KCNJ5 mutations, functional characterization of this mutation showed Na+-dependent cell membrane depolarization and increased intracellular Ca2+ concentration causing high CYP11B2 expression.23FH-3 Type BIn 2012, 2 studies independently reported the G151E germline mutation in patients with a milder form of hyperaldosteronism.19,24 These patients had no evidence of adrenal hyperplasia, and their hypertension could be easily controlled with drugs.24 In vitro, the mutation showed prominent effects featuring a large Na+ conductance with rapid Na+-dependent cell lethality. To explain these paradoxical findings, it was contended that the Na+ influx-dependent cell death could limit the expansion of zona glomerulosa cell mass, thus preventing the development of hyperplasia with ensuing less-prominent PA. Hence, it was suggested that the overproduction of aldosterone in the surviving zona glomerulosa cells might be sufficient to raise blood pressure but not high enough to render hypertension resistant to drug treatment.Another germline mutation (Y152C) was detected in a patient with mild form of hyperaldosteronism because of an adrenal adenoma, but it remains unclear whether this is another familial form or a sporadic de novo mutation because no information on other family members was given.23FH Type 4A recurrent germline gain-of-function mutation in CACNA1H gene (M1549V) was identified in 5 children with PA before 10 years of age as the cause of FH type 4 (Table). The mutation was inherited in 3 of the cases and occurred de novo in 2.25 All patients showed hyperaldosteronism with low plasma renin activity but no evidence of mass or hyperplasia on adrenal imaging at the time of presentation. There were no recurrent or distinctive features in the index cases, for example, history of seizures or neurological or neuromuscular disorders.CACNA1H gene is located on chromosome 16p13 and encodes the pore-forming α1 subunit of the T-type voltage-dependent calcium channel Cav3.2. CACNA1H is highly expressed in the adrenal zona glomerulosa and is activated at slightly depolarized potentials. Of note, the Cav3.2 channel is involved in the zona glomerulosa membrane potential oscillations and aldosterone production, according to Barrett et al.26Whole-cell patch-clamp experiments in human embryonic kidney-293 cells showed that the M1549V CACNA1H channel exhibited activation to less-depolarized potentials and slow inactivation—2 features held to cause enhanced Ca2+ influx in adrenal glomerulosa cells. The overexpression of M1549V in HAC15 adrenocortical cells mutant channel increased CYP11B2 gene expression and aldosterone production in basal conditions (Figure 1D), whereas cotreatment with the T-type calcium channel blocker mibefradil abolished aldosterone production, indicating that M1549V CACNA1H mutation induces autonomous aldosterone production via T-type calcium channels.Four additional germline CACNA1H mutations in patients with PA and different clinical features were identified by Daniil et al.27 A M1549I de novo mutation occurred in the same position of M1549V and caused hypertension and hyperaldosteronism alongside mild mental retardation, social skill alterations, learning disabilities, and development disorders. The S196L and P2083L were identified in 2 families affected by hypertension and PA. The V1951E germline variant was also identified in a patient with APA, cured by unilateral adrenalectomy.In vitro electrophysiological experiments demonstrated that these new CACNA1H mutations changed the electrophysiological properties of the channel similar to M1549V.25 Furthermore, transfections of mutant in H295R-S2 cells induced high aldosterone levels and overexpression of genes coding for steroidogenic enzymes after K+ stimulation.Primary Aldosteronism With Seizures and Neurologic Abnormalities SyndromeThe primary aldosteronism with seizures and neurologic abnormalities syndrome (OMIM: 615474) phenotype (Table) was the first calcium channel mutation found to be associated with extra adrenal symptoms.28 Two de novo germline mutations (I770M and G403D) in the CACNA1D gene were detected in 2 children with severe hypertension diagnosed at birth, hypokalemia, and neurological manifestations, including seizures and cerebral palsy.28 This gene, located on chromosome 3p14.3, encodes for Cav1.3—the α subunit of the L-type voltage-gated calcium channel. Both are gain-of-function mutations and had already been found in sporadic forms of APA.28,29 They cause channel activation at membrane potentials close to the resting of the zona glomerulosa cells (−80 mV) and increase Ca2+ influx and stimulation of aldosterone production (Figure 1D).Conclusions and PerspectivesThe last decade has witnessed enormous progresses in understanding the molecular basis of human PA, both its sporadic (reviewed elsewhere18) and its familial forms. Genetic testing is already available for FH-1—the first familial form to be clarified at the molecular level—as well as for the other forms. In some forms of FH, this progress already opened the way to personalized treatment. For example, as mentioned above, the reason why low-dose dexamethasone is highly effective in correcting PA and lowering blood pressure in FH-1 not only received an explanation at the molecular level but also has allowed pinpointing which patients with familial PA should receive this therapy. This field has received further impulse from the more recent discovery that the altered electrophysiology caused by the KCNJ5 mutations L168R and G151R can be specifically corrected in vitro30 and ex vivo31 with macrolides antibiotics. In fact, these findings can open the way to personalized diagnosis and treatment of PA caused by these mutations—a hypothesis now being tested in the MAPA study (Macrolides for KCNJ5-Mutated Aldosterone-Producing Adenoma)32 and to be further explored in the same patients with FH-3. As molecular, electrophysiological, and pharmacological research will be further expanded, there is no doubt that the development of specific drugs interfering with the function of mutated channels could be foreseen in the near future as a personalized treatment for the other familial forms.Sources of FundingThis work was supported by research grants from the International PhD Program in Arterial Hypertension and Vascular Biology of the University of Padova, and the Foundation for Advanced Research in Hypertension and Cardiovascular Diseases (to G.P. Rossi).DisclosuresNone.FootnotesCorrespondence to Gian Paolo Rossi, Department of Medicine, Hypertension Unit, University Hospital of Padova, Via Giustiniani, 2, 35126 Padova, Italy. E-mail [email protected]References1. Litynski M. [Hypertension caused by tumors of the adrenal cortex].Pol Tyg Lek (Wars). 1953; 8:204–208.MedlineGoogle Scholar2. Conn JW. 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Dominiczak A, Kuo D, Bhalla V, Granger J and Griffin K (2018) Celebrating 40 Years of Accomplishments, Hypertension, 73:1, (3-6), Online publication date: 1-Jan-2019. June 2018Vol 71, Issue 6 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.118.11150PMID: 29735637 Originally publishedMay 7, 2018 PDF download Advertisement SubjectsGeneticsHypertension
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