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Published in final edited form as: Curr Opin Endocr Metab Res. 2019 Aug 9;8:104–111. doi: 10.1016/j.coemr.2019.07.010

Molecular mechanisms of ARMC5 mutations in adrenal pathophysiology

Constantine A Stratakis 1, Annabel Berthon 1,*
PMCID: PMC7448540  NIHMSID: NIHMS1539706  PMID: 32864505

Abstract

Since the initial discovery of mutations in the Armadillo-containing repeat protein 5 gene (ARMC5) in primary bilateral macronodular adrenocortical hyperplasia (PBMAH), efforts have been made to better understand the molecular mechanisms involving ARMC5 in the development of this rare form of Cushing syndrome. It has now been established that germline ARMC5-inactivating mutations, mostly frameshift and nonsense ones, are responsible for roughly 40% of PBMAH cases. ARMC5 is a tumor suppressor gene responsible for a familial form of PBMAH. Furthermore, the presence of inactivating ARMC5 mutations is associated with a more severe CS and hypertension as well as an overall increase in adrenal mass. However, ARMC5 inactivation decreases cortisol secretion both in vitro and in vivo (in mice) suggesting that the way that ARMC5 deficiency leads to Cushing syndrome is complicated and maybe not a direct effect of the ARMC5’s loss, requiring additional molecular events to take place. Moreover, in silico predicted damaging ARMC5 variants have been identified in patients of African American descent with primary aldosteronism suggesting a potential role of ARMC5 in predisposing to low renin hypertension. Beyond its role in adrenocortical cells, ARMC5 defects has recently been associated with meningioma and T-cell immune response defects in humans and mice, respectively. Herein, we review recent discoveries in ARMC5’s role in adrenal pathophysiology and beyond; clearly, we are only at the beginning of understanding the function of this gene with functions in the adrenal gland, the immune system, and elsewhere.

Keywords: Adrenocortical hyperplasia, ARMC5, Cushing syndrome, Cortisol

Introduction

Primary macronodular adrenocortical hyperplasia (PBMAH) is a bilateral process characterized by the presence of macronodules larger than 10 mm in diameter. PBMAH often but not always leads to significant hypercortisolemia and corticotropin-independent Cushing syndrome (CS). PBMAH grows slowly and higher cortisol levels develop progressively; it is often diagnosed in patients between 40 and 60 years old (y.o.). Although PBMAH was first associated with aberrant G-protein receptor signaling [1–4], the bilateral nature of adrenal hyperplasia and the description of familial cases suggested that it was genetic in origin. Indeed, in 2013, Assié et al. reported mutations in a gene called ARMC5 for Armadillo repeat-containing protein 5. In this initial study, germline ARMC5 mutations were associated with loss of heterozygosity (LOH) or nonsense mutations in nodules in 18 out of the 33 patients (55%) [5]; ARMC5 genetic alterations followed the Knudson’s two-hit model characteristic of a tumor suppressor gene. A number of studies since, in multiple independent cohorts of PBMAH patients, have confirmed that germline ARMC5 mutations are found in 25 to 50% of all patients with PBMAH[6–15].

Inactivation of ARMC5

Interestingly, different studies in which several nodules from the same patient have been sequenced for ARMC5 revealed the presence of individual somatic mutations in each nodule with one patient presenting with up to 15 different mutations (1 germline and 14 somatic ones) [5, 6, 8–10, 12]. This amazing number of somatic ARMC5 genetic variations found in a single patient suggests that ARMC5 deficiency causes a genomic instability even if PBMAH is a benign disorder without malignant progression. To our knowledge, to date, 99 mutations (summarized in Table 1) have been identified along the length of the ARMC5 protein including but not limited to its two protein-protein interaction domains characteristic of the ARMC protein family, the Armadillo and the BTB/POZ domain [16] (Table 1). The absence of a “hotspot” in the ARMC5 gene suggests that both protein-protein domains should be functional to prevent the development of this adrenocortical disorder. As previously demonstrated for others ARMC proteins, we can hypothesize that ARMC5’s function is dependent of its protein-protein interaction network.

Table 1:

Frameshift (A), nonsense (B) and missense (C) ARMC5 mutations identified in PBMAH patients. N/A: Not Available. The location of variants has been described on the transcript ENST00000268314.8/NM00115247. DANN score is a scoring methology ranging from 0 to 1 with 1 being the most pathogenic [31]. The allele frequence is based on the gnomAD exosomes.

A. cDNA Protein Domain Allele Number of index PBMAH cases References
c.164_165insG p.A55fs - Somatic 1 Elbelt et al., 2014
- p.G57Efs*80 - Germline 1 Assie et al., 2013; Espiard et al., 2015
- p.G57Gfs*45 - Germline 1 Gagliardi et al., 2014
- p.I58Nfs*45 - Germline 1 Alencar et al., 2014
c.174dupC p.E59Rfs*44 - Germline 1 Albiger et al., 2016
c.194delG p.G65Afs*72 - Germline 1 Albiger et al., 2016
- p.A72Lfs*36 - Somatic 1 Assie et al., 2013; Espiard et al., 2015
c.220_222delinsTT p.L74Ffs*63 - Germline 1 Albiger et al., 2016
- p.A80G(;)S82Vfs*5 - Somatic 1 Espiard et al., 2015
- p.A83Rfs*51 - Somatic 1 Alencar et al., 2014
- p.P93Rfs*40 - Somatic 1 Assie et al., 2013; Espiard et al., 2015
- p.A97Gfs*4 - Somatic 1 Alencar et al., 2014
c.305_341del p.S102fs - Somatic 1 Elbelt et al., 2014
c.311delC p.A104fs - Somatic 1 Elbelt et al., 2014
- p.A104Gfs*7 - Germline 2 Assie et al., 2013; Espiard et al., 2015
c.315_316insG p.A106fs - Somatic 1 Elbelt et al., 2014
- p.A106Rfs*31 - Germline 1 Espiard et al., 2015
- p.S107Gfs*8 - Somatic 1 Assie et al., 2013
c.325_326delinsT p.P109Sfs*28 - Somatic 1 Albiger et al., 2016
c.323_324insC p.A110fs*9 - Germline 2 Elbelt et al., 2014; Bourdeau et al., 2016
c.327delC p.A110Pfs*27 - Somatic 2 Assie et al., 2013; Espiard et al., 2015; Correa et al., 2015
c.346delT p.S116Rfs*21 - Somatic 1 Correa et al., 2015
c.456–475+5del28 Armadillo Somatic 1 Assie et al., 2013
c.608delG p.S203Tfs*2 Armadillo Somatic 1 Correa et al., 2015
- p.A206Dfs*22 Armadillo Somatic 1 Assie et al., 2013; Espiard et al., 2015
- p.L220Sfs*35 Armadillo Somatic 1 Espiard et al., 2015
c.789_808del20 p.E264Pfs*5 Armadillo Somatic 1 Correa et al., 2015
- p.A296Cfs*34 Armadillo Germline 1 Assie et al., 2013; Espiard et al., 2015
c.1042delC p.L348Wfs*27 Armadillo Somatic 1 Albiger et al., 2016
c.1330delA p.T444Pfs*16 Armadillo Germline 1 Gagliardi et al., 2014
- p.A492Pfs*52 - Somatic 1 Assie et al., 2013; Espiard et al., 2015
c.1506_1507delCA p.R502fs - Somatic 1 Elbelt et al., 2014
c.1735–1738delTGCC p.C579Sfs*49 - Germline 1 Faucz et al., 2014
- p.V584Afs*19 - Somatic 1 Assie et al., 2013; Espiard et al., 2015
- p.A702_S706del - Germline 1 Assie et al., 2013; Espiard et al., 2015
- p.F700del - N/A 1 Assie et al., 2013; Espiard et al., 2015
- p.L705Ffs*12 - Somatic 1 Espiard et al., 2015
- p.L708Pfs*9 - Somatic 1 Espiard et al., 2015
c.2139delT p.T715Lfs*1 - Germline 1 Gagliardi et al., 2014
c.2444delG p.A815Lfs*102 BTB Somatic 1 Correa et al., 2015
B. cDNA Protein Domain SNP Allele Number of index PBMAH cases References
c.−117 A>C - - rs76210462 Germline 1 Albiger et al., 2016
c.91A>T p.K31X - - N/A 1 Assie et al., 2013; Espiard et al., 2015
c.118_120delCTGinsTGA p.L40X - - Somatic 1 Assie et al., 2013; Espiard et al., 2015
c.226 C>T p.R76X - rs1340161811 Somatic 1 Assie et al., 2013; Espiard et al., 2015
c.256 C>T p.Q86X - rs587777660 Germline 1 Assie et al., 2013; Espiard et al., 2015
c.453–475+5del28 - - - Somatic 1 Espiard et al., 2015
c.517C>T p.R173X - - Germline 2 Berthon et al., 2019; Liu et al., 2018
c.703C>T p.Q235X - - Somatic 2 Espiard et al., 2015; Berthon et al., 2019
c.799C>T p.R267X Armadillo rs369721476 Germline 4 Assie et al., 2013; Espiard et al., 2015
c.807C>A p.C269X Armadillo - Somatic 1 Correa et al., 2015
c.1033 C>T p.Q345X Armadillo - Somatic 1 Correa et al., 2015
c.1059 C>A p.C353X Armadillo - Somatic 1 Correa et al., 2015
c.1090 C>T p.R364X Armadillo rs1386368908 Germline 3 Albiger et al., 2016; Faucz et al., 2014
c.1158 G>A p.W386X Armadillo - Germline 1 Alencar et al., 2014
c.1288 G>T p.E430X - - N/A 1 Assie et al., 2013; Espiard et al., 2015
c.1297 G>T p.E433X - - Somatic 1 Elbelt et al., 2014
c.1428 G>A p.W476X - - Germline 1 Correa et al., 2015
c.1712C>G p.S571X - - Somatic 1 Berthon et al., 2019
c.1855 C>T p.R619X - rs766717248 Germline/Somatic 1 Assie et al., 2013; Espiard et al., 2015
c.1960 C>T p.R654X - rs1379678857 Somatic 1 Elbelt et al., 2014
c.2029 G>T p.E677X - - Somatic 1 Bourdeau et al., 2016
c.2290 C>T p.R764X BTB rs778422149 Germline 3 Albiger et al., 2016; Espiard et al., 2015
c.2336 C>G p.S779X BTB - Germline 1 Alencar et al., 2014
C. cDNA Protein Domain SNP Allele Prediction DANN score Results of in vitro testing Number of index PBMAH cases Allele frequency References
c.*234_*238dup - 3’UTR rs142544346 Germline - - - 1 0.03943 Albiger et al., 2016
c.41 T>A p.F14Y - rs151069962 Germline Missense 0.9271 - 2 0.048 Faucz et al., 2014
c.167 G>C p.G56A - rs780112907 Germline Missense 0.9586 - 1 0 Albiger et al., 2016
c.247G>C p.A83P - - Somatic Missense 0.9852 - 1 - Correa et al., 2015
c.343 T>C p.S115P - rs199693319 Germline Missense 0.3845 - 1 0.0007388 Faucz et al., 2014
c.415T>C p.C139R - - Somatic Missense - Pathogenic 1 - Assie et al., 2013; Espiard et al., 2015
c.446 C>T p.L156F Armadillo rs114930262 Germline Missense 0.9934 - 1 0.001592 Faucz et al., 2014
c.476–1G>A - Armadillo - Somatic Splice site 0.9945 - 1 - Correa et al., 2015
c.508 A>G p.I170V Armadillo rs35923277 Germline Missense 0.9981 - 6 0.03638 Faucz et al., 2014
c.943 C>T p.R315W Armadillo Somatic/Germline Missense 0.9989 Pathogenic 2 4.096E-06 Assie et al., 2013; Espiard et al., 2015; Gagliardi et al., 2014
c.944 G>A p.R315Q Armadillo rs1415974570 Germline Missense 0.9994 - 1 4.096E-06 Faucz et al., 2014
c.952C>G p.L318V Armadillo rs1293014259 Germline Missense 0.9929 - 1 8.198E-06 Alencar et al., 2014
c.992T>C p.L331P Armadillo - Somatic Missense 0.9978 Pathogenic 1 - Assie et al., 2013; Espiard et al., 2015
c.1084 C>T p.R362W Armadillo rs1385397608 Germline/Somatic Missense 0.9992 - 2 0.00003232 Albiger et al., 2016; Elbelt et al., 2014
c.1085G>T p.R362L Armadillo - Somatic Missense 0.9985 Pathogenic 1 - Assie et al., 2013; Espiard et al., 2015
c.1094T>C p.L365P Armadillo rs587777663 Germline Missense 0.9987 - 1 - Alencar et al., 2014
c.1181T>C p.L394P Armadillo - Germline Missense 0.9989 - 1 - Alencar et al., 2014
c.1448 C>T p.P483L - rs552657393 Germline Missense 0.6814 - 1 0.00003085 Albiger et al., 2016
c.1643T>C p.L548P - rs587777661 Germline Missense 0.9973 Pathogenic 1 - Assie et al., 2013; Espiard et al., 2015
c.1739 T>C p.L580P - - Germline Missense 0.9989 - 1 - Albiger et al., 2016
c.1751T>A p.V584E - - Somatic Missense 0.9909 - 1 - Correa et al., 2015
c.1777 C>T p.R593W - rs587777662 Germline Missense 0.9989 - 2 0.00003236 Faucz et al., 2014; Gagliardi et al., 2014
c.1969T>C p.C657R - - Germline Missense 0.9972 Pathogenic 1 - Assie et al., 2013; Espiard et al., 2015
c.1971C>G p.C657W - - Somatic Missense 0.9711 - 1 - Alencar et al., 2014
c.1975 C>T 1 p.R659C - rs759844590 Germline Missense 0.2974 - 1 4.079E-06 Albiger et al., 2016
c.1991T>G p.I664S - - Germline Missense 0.9947 Pathogenic 1 - Espiard et al., 2015
c.2114 C>T 2 p.A705V - rs11150624 Germline Missense 0.3192 - 1 0.3375 Bourdeau et al., 2016
c.2192 C>G p.P731R - rs200951744 Germline Missense 0.9943 - 1 0.001357 Albiger et al., 2016
c.2207A>C p.Y736S - - Somatic Missense 0.9922 Pathogenic 1 - Assie et al., 2013; Espiard et al., 2015
c.2228C>T p.A743V BTB - Somatic Missense 0.9974 - 1 - Correa et al., 2015
c.2261T>C p.L754P BTB - Germline Missense 0.9991 Pathogenic 1 - Espiard et al., 2015
c.2393 G>C p.G798A BTB rs115611533 Germline Missense 0.2099 - 2 0.008979 Faucz et al., 2014
c.2405C>G p.P802R BTB - Somatic Missense 0.9982 - 1 - Correa et al., 2015
c.2423A>C p.H808P BTB - Germline Missense 0.9857 - 1 - Alencar et al., 2014
c.2692C>T p.R898W - rs587777659 Germline Missense 0.9992 Pathogenic 4 9.825E-06 Assie et al., 2013; Espiard et al., 2015; Faucz et al., 2014
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1, 2

Variants located on the transcript ENST00000457010.6/NM_024742; the equivalent on the transcript NM_001105247c.1864+111C>G and c.1864+250C>T, respectively.

Forty different frameshift, 21 nonsense mutations and multiple cases of LOH have been described (Table 1) supporting an inactivating role of these alterations either due to the absence or the expression of an inactive ARMC5 protein. However, as ARMC5’s molecular function remains unclear, it is more difficult to determine the potential deleterious of missense variants identified in the germline of patients with PBMAH. Most of the genetic studies focused then, on missense variants present in less than 1% of the general population and that were predicted in silico to be damaging using several software (Table 1). Moreover, the pathogenicity of 10 missense and one amino-acid deletion identified in PBMAH patients has been established in vitro through their inability to induce apoptosis after overexpression in the human adrenocortical cell line, H295R in contrast with wild-type ARMC5 (Table 1) [5, 9]. However, to our knowledge, the deleterious potential of 23 missense variants including 18 identified at germline level remains to be established, which would be essential especially because ARMC5 mutation is a frequent cause of familial form of PBMAH. Indeed, since the first discovery of ARMC5 mutations, twelve independent families have been reported for presenting an association between the presence of germline ARMC5 mutations and the development of CS in family members up to three generations [6, 10, 13, 14, 17–19]. Interestingly, almost all ARMC5 carriers in these different families present hormonal abnormalities either overt or subclinical CS and/or adrenal nodules in imaging. The penetrance of the disease sounds therefore, high in ARMC5 carriers even if the severity varies between the relative and the index cases. This difference may reflect earlier stages of PBMAH found in relatives studied at younger ages as this disorder is usually diagnosed between 50–60 y.o.. However, it also suggests that other factors than the germline mutation shared by all the related carriers such as the number and the type of somatic mutations acquired may control disease progression. More generally, the phenotypic variability and the presence of subclinical CS (which is more difficult to detect) suggests that the prevalence of familial PBMAH may be underestimated. It is, therefore, necessary to establish the pathogenicity of all ARMC5 missense variants that have been identified in patients with PBMAH and their families to offer proper counseling.

Characteristic of ARMC5-mutated PBMAH

As PBMAH has first been associated with aberrant expression of G-protein receptors (GPCR), we can wonder if there is a relation between the loss of ARMC5 function and the abnormal expression of GPCR in PMAH. Whereas none of food-dependent CS patients studied harbors ARMC5 mutations, its loss of function has been associated with abnormal response to upright posture, vasopressin and metopramide test [5, 9, 17]. Moreover, it has been reported in a large ARMC5 family including 9 clearly affected members out of 28 that all affected members present a similar aberrant β-adrenergic and V1-vasopressin receptors. The potential relationship between the germline ARMC5 mutation (p.A110Rfs*9) that has previously been identified in PBMAH patients and this pattern remains to be clarified. Interestingly, Alpha-2 adrenergic receptor (Adra2a) and Arginine vasopressin receptor 1a (Avpr1a) are overexpressed in the adrenal cortex of 12 months Armc5+/− mice [20] supporting the hypothesis that ARMC5 inactivation could be directly responsible for their overexpression.

While ARMC5 mutations have been discovered in PBMAH, its molecular function remains unknown. An initial transcriptomic studies performed on 5 PBMAH with and 5 without ARMC5 mutations demonstrates that PBMAH cases could be classified in two groups depending their genotype based on their transcriptomic profiles by unsupervised clustering [5]. As previously suggesting by the sequencing data, ARMC5-inactivating mutations then, drive the development of a subset of PBMAH cases presenting a particular clinical profile. Indeed, three independent studies comparing the clinical data between index patients with and without ARMC5 deleterious mutations demonstrates association between ARMC5 inactivation and a diagnosis for overt CS and more severe hypertension [7, 9, 12]. This predominance of overt CS in mutated patients can be explained by their significantly higher late-night cortisol and ACTH suppression found in two of these studies [7, 9]. Similarly, whereas Espiard et al. identified an association between ARMC5 deleterious mutations and early diagnosis in a cohort of 92 patients (24 mutated and 68 wild-type), this could not be confirmed in the Albiger and Faucz studies that analyzed smaller cohort with 53 (12 mutated and 41 wild-type cases) and 34 (7 mutated and 27 wild-type) cases, respectively [12, 21]. The smaller cohort studied may also explain why the association observed between the presence of ARMC5 mutations and the increase in adrenal size either after surgery or by CT measurement was not found in Faucz et al. [7, 9, 12]. Altogether, these transcriptomic and clinical data suggest that ARMC5 controls the adrenocortical steroidogenesis and cellular growth.

ARMC5 function in adrenocortical cells

The first molecular analysis to identify the molecular mechanism involving ARMC5 in the adrenocortical cells were performed using the human adrenocortical cell line, H295R. Knockdown ARMC5 using siRNA in H295R led to a decrease of CYP17A1 and CYP21A2 mRNA accumulation both in basal and forskolin-induced conditions, leading ultimately to a decrease in cortisol secretion [5]. Similar results were obtained in cell cultures from wild-type PBMAH nodules silenced for ARMC5 [22]. Interestingly, the different PBMAH nodules cultured showed down-regulation of the steroidogenic enzymes compared to normal adrenal tissues, independently of the ARMC5 sequence status, demonstrating a relative inefficiency of steroidogenesis in PBMAH.

These results are, however, surprising given the association between ARMC5-inactivating mutations and higher cortisol levels in patients. It was hypothesized that the relative inefficiency to produce cortisol in ARMC5-mutated cells may be compensated by the bigger adrenal mass observed in patients with PBMAH. This hypothesis is supported by the absence of high cortisol levels in early stages of the disease in ARMC5-mutation carriers in families with PBMAH [6, 10]. Interestingly, mouse heterozygotes for Armc5 (and, therefore, genetically close to PBMAH patients) present initially with lower corticosterone levels; their hypocorticosteronemia is associated with decreased expression of steroidogenic enzymes similar to the one observed in vitro after ARMC5 silencing [20]. However, their corticosterone levels significantly increased at 18 months of age, even if they never developed adrenocortical masses. Similarly, Armc5 homozygote knockout mouse develop hypercorticosteronism at 16 months without any associated adrenocortical tumors [23]. Altogether, these murine data suggest that ARMC5 may differently regulate steroidogenesis in the aging adrenal gland. These data also suggest that additional genetic or other events may be needed for both higher glucocorticoid levels and adrenocortical masses to develop in mice and humans with ARMC5 haploinsufficiency.

The dramatic increase in adrenal mass characteristic of PBMAH can be at least in part, caused by the loss of the pro-apoptotic role of ARMC5 identified in the malignant adrenocortical cells, H295R (see above) [5, 9]. Consistently, overexpression of ARMC5 induced apoptosis in both mutant and non-mutant cultured PBMAH nodules. Moreover, an increase in proliferation is also observed following ARMC5 silencing in non-mutated cultures nodules [22] suggesting that development of macronodules may result from a combination of decrease in apoptosis and an increase in proliferation.

ARMC5 in primary aldosteronism patients

Beyond the important role played by ARMC5 inactivation in PBMAH development, Zilbermint et al. have first investigated its potential involvement in patients presenting different adrenocortical disorders resulting to a primary aldosteronism (PA) [24]. As previously demonstrated for another Armadillo repeats-containing protein, β-catenin, which is activated in both aldosterone- and cortisol-producing adrenocortical tumors [25–27], they identified 12 germline ARMC5 variants in a cohort of 56 PA patients [24]. Out of these 12, one splicing and 4 missense variants including one previously identified in PBMAH patients (p.R898W) are in silico predicted to be damaging. Whereas no somatic mutations were observed in the 3 sequenced tumors, ARMC5 expression was decreased in the 2 tumors presenting a predicted damaging variant compared to tumor without mutation. These results suggest that germline ARMC5 variants may modulate ARMC5 expression in PA as previously observed in PBMAH [5, 7] even in the absence of a second mutation and this could participate in the cause of aldosterone hypersecretion. Consistently, few ARMC5 mutated PBMAH cases presenting an aldosterone excess have been reported [11, 19]. The 5 predicted damaging ARMC5 variants are harbored by 8 PA patients that were all African Americans. Indeed, Africans Americans are affected by higher rates of hypertension than Caucasians due to largely unclear genetic and other causes that may involve dysregulation of aldosterone secretion [28]. In a smaller study, there were no predicted damaging ARMC5 variants in a cohort of 37 Caucasians and 2 PA patients of African-American descent [29] and in 4 families with familial hyperaldosteronism type II [30].

ARMC5 extra-adrenal function

ARMC5 is a well conserved protein during the evolution supporting an important role of ARMC5 gene for development and/or survival of the early embryo. Interestingly, one of the 4 ARMC5 human isoforms is ubiquitously expressed in human tissues [16] suggesting that the consequences of ARMC5 mutations may not be limited to the adrenal cortex. Consistently, the two whole-body Armc5 homozygote knockout mice that have been generated show lethality in early stages of embryonic development [20, 23]. When Armc5 knockout mice survive, they have a drastic decrease in body weight and length [20, 23]. Moreover, using their mouse model, Hu et al. demonstrated that Armc5 played an important role in the T-cell proliferation and differentiation, its invalidation compromises then, their immune response [23]. Based on these data, we can wonder if germline ARMC5 mutations may lead to extra-adrenal phenotype in PBMAH patients.

In 2015, a family with PBMAH caused by a germline frameshift mutation (p.A110fs*9) was investigated: a carrier had both a meningioma and PBMAH; a pancreatic tumor was also present. Interestingly, whereas the pancreatic tumor did not show another ARMC5 mutation or LOH, the meningioma harbored a somatic ARMC5 mutation (p.R502fs) [10]. An additional family, with 3 of the 7 members presenting with a meningioma was then reported [6, 8]. In addition, given the mouse data, further studies are needed for the role of ARMC5 in regulating immune responses in humans and mice [16].

Conclusions

Since the first discovery of ARMC5 mutations causing PBMAH, important efforts have been made to establish the importance of the ARMC5 protein in the regulation of adrenocortical homeostasis. Nevertheless, there is still a need for better understanding of ARMC5 protein partners and signaling regulation that leads to Cushing syndrome in humans. Elucidation of the mechanisms through which ARMC5 controls steroidogenesis in the adrenal cortex may lead to the development of medical treatments for patients with PBMAH or hyperaldosteronism. Finally, it is possible that ARMC5 defects are involved in other pathology, from the immune system to tumor of the nervous system (meningioma); additional studies are needed to clarify this possibility, too.

Acknowledgments

FUNDING: This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD).

Footnotes

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Conflict of interest

The authors have declared that they do not have any conflict of interest.

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