ARMC5

Official Full Name

armadillo repeat containing 5

Organism

Homo sapiens

GeneID

79798

Background

This gene encodes a member of the ARM (armadillo/beta-catenin-like repeat) superfamily. The ARM repeat is a tandemly repeated sequence motif with approximately 40 amino acid long. This repeat is implicated in mediating protein-protein interactions. The encoded protein contains seven ARM repeats. Mutations in this gene are associated with primary bilateral macronodular adrenal hyperplasia, which is also known as ACTH-independent macronodular adrenal hyperplasia 2. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2014]

Synonyms

AIMAH2;

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Detailed Information

The mutation of ARMC5 (armadillo repeat containing 5) is closely related to primary bilateral macronodular adrenal hyperplasia (PBMAH). Recent studies have shown that ARMC5 forms adrenal nodules by reducing apoptosis, regulating the steroidogenic synthesis and increased cortisol secretion. So far, little is known about the structure or function of ARMC5. It is now clear that all members of the ARM family include two domains, and these two domains are highly conserved from fruit flies to humans. The presence of these domains suggests that ARMC5 can interact with a variety of proteins to participate in biological processes, as studies have observed that ARMC5 mutations in PBMAH are associated with specific expression patterns of abnormal G-protein coupled receptors (GPCRs). However, because the specific structure of ARMC5 and the recognition mechanism of target proteins are not fully understood, the function of the protein encoded by ARMC5 is still unpredictable. According to existing literature, ARMC5 is closely related to the occurrence of adrenal-related hypertension.

Alencar et al. performed a full exome sequencing on 47 patients with PBMAH in a Brazilian family, confirming the presence of the ARMC5 gene mutation. At the same time, no mutation was found in 125 randomly selected healthy individuals. This suggests that the ARMC5 mutation is a susceptible gene for PBMAH. Three subsequent studies of familial PBMAH cases further confirmed that mutations in the ARMC5 gene are a common cause of familial PBMAH. De et al. found that ARMC5 mutations cause abnormal secretion of cortisol in PBMAH patients by regulating hormone receptors that are abnormally expressed in the adrenal gland. The further explanation that ARMC5 is a causative gene of the PBMAH family. A comprehensive study has reported that the ARMC5 gene mutation accounts for approximately 50% of patients with PBMAH.

ARMC5 Is Involved in Other Adrenal-related Hypertension

Mulatero et al. suggested that the ARMC5 mutation may be associated with Afro-hypertension with low-renal aldosteronism. In this study, a cohort of 56 patients with primary aldosteronism showed that 10.7% of ARMC5 mutations were present in African-American patients, and the mutation was found to be pathogenic by bioinformatics prediction. This suggests that the ARMC5 germline mutation may be associated with primary aldosteronism. In addition, studies have shown that ARMC5 mutations are also present in meningioma patients. Studies have shown that some adults carry ARMC5 mutations by screening for familial adrenal microscopic lesions. Okazawa found ARMC5 somatic mutations in meningioma tissue DNA from meningioma patients, further demonstrating that ARMC5 mutations are associated with the development of meningioma. In addition, there is a long time to find that 3/7 of the 7 members of the same family (43%) due to the ARMC5 mutation, the presence of adrenal cortical nodular hyperplasia and meningioma, it is believed that ARMC5 mutation can cause PBMAH and meningioma.

ARMC5 Figure 1. Effects of ARMC5 involved in adrenal tumorigenesis. (Drougat, et al. 2015)

The Relationship Between the type of Mutation and Phenotype of ARMC5 in PBMAH

Among the data reported, the ARMC5 gene mutation types include 29 germline mutations and 32 somatic mutations. Two novel mutations were found in the tumor tissue DNA, but it was not determined whether the two mutations were germline mutations or somatic mutations. Only a small proportion of these mutations are present in familial cases. The ARMC5 mutation accounts for 25-50% of patients with PBMAH without a clear family history or related tumors, suggesting that most of the pathogenic mutations are sporadic, but whether it is significantly associated with familial aggregation has been studied.

Studies by Assie et al. and Faucz found that ARMC5 gene defects are associated with the severity of clinical manifestations of PBMAH. Patients with ARMC5 mutations often have high blood pressure, higher cortisol levels, and larger diameter adrenal nodules in CT, and they are more likely to undergo surgery than non-mutated patients. Espiard et al. studied 98 patients with different severity of PBMAH, further indicating that the AMMC5 mutation causes PBMAH to be associated with abnormal expression of specific receptors.

ARMC5 Possible Mechanisms Involved in the Pathogenesis of PBMAH

The discovery of the ARMC5 gene has opened up new horizons for the development and development of PBMAH. The onset of PBMAH is consistent with the "two-hit-model" model: a secondary mutation of the ARMC5 in the absence of adrenocortical cell regulation leading to the appearance of nodular hyperplasia. Preliminary studies have shown that ARMC5 causes adrenal-related hypertension mainly through the following two aspects: On the one hand, normal ARMC5 protein overexpression induces premature death of adrenal cortical cells. The ARMC5 missense mutant loses the ability to induce apoptosis, resulting in the formation of adrenal nodular hyperplasia. On the other hand, by inactivating ARMC5 expression with siRNA in vitro, expression of various major steroid synthesis elements in adrenocortical cells is altered. In addition, in the ARMC5-deficient cells, the mRNA levels of the MC2R receptor, the expression of the SF1 transcription factor and the steroid synthase CYP17 and CYP21 were decreased. Therefore, to further clarify the mechanism and characteristics of ARMC5, it is necessary to study the molecular mechanism of adrenal-related hypertension such as PBMAH.

References:

Alencar, G. A., Lerario, A. M., Nishi, M. Y., Mariani, B. M., Almeida, M. Q., & Tremblay, J., et al. (2014). Armc5 mutations are a frequent cause of primary macronodular adrenal hyperplasia. Journal of Clinical Endocrinology & Metabolism, 99(8), E1501.
De, V. A., Alencar, G. A., Bourdeau, I., Fragoso, M. C., & Lacroix, A. (2014). Primary bilateral macronodular adrenal hyperplasia. Current Opinion in Endocrinology Diabetes & Obesity, 21(3), 177.
Assié, G., Libé, R., Espiard, S., Rizk-Rabin, M., Guimier, A., & Luscap, W., et al. (2013). Armc5 mutations in macronodular adrenal hyperplasia with cushing's syndrome. New England Journal of Medicine, 369(22), 2105.
Faucz, F. R., Zilbermint, M., Lodish, M. B., Szarek, E., Trivellin, G., & Sinaii, N., et al. (2014). Macronodular adrenal hyperplasia due to mutations in an armadillo repeat containing 5 (armc5) gene: a clinical and genetic investigation. Journal of Clinical Endocrinology & Metabolism, 99(6), E1113.
Espiard, S., Drougat, L., Libé, R., Assié, G., Perlemoine, K., & Guignat, L., et al. (2015). Armc5 mutations in a large cohort of primary macronodular adrenal hyperplasia: clinical and functional consequences. Journal of Clinical Endocrinology & Metabolism, 100(6), E926.
Mulatero, P., Schiavi, F., Williams, T. A., Monticone, S., Barbon, G., & Opocher, G., et al. (2016). Armc5 mutation analysis in patients with primary aldosteronism and bilateral adrenal lesions. Journal of Human Hypertension, 30(6), 374.
Okazawa, T. (2013). Intraadrenal corticotropin in bilateral macronodular adrenal hyperplasia. New England Journal of Medicine, 369(22), 2115-25.
Drougat, L., Omeiri, H., Lefèvre, L., & Ragazzon, B. (2015). Novel insights into the genetics and pathophysiology of adrenocortical tumors. Frontiers in Endocrinology, 6, 96.

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