Balkan Journal of Medical Genetics

A PILOT STUDY OF ANXA2, MED12, CALM1 AND MAPK1 GENE VARIANTS IN PRIMARY HYPERPARATHYROIDISM
Chorti A#1, Achilla C#2, Siasiaridis A2, Aristeidis I1, Cheva A3, Theodosios Papavramidis T##1, Chatzikyriakidou A##*2,4
*Corresponding Author: *Corresponding Author: Anthoula Chatzikyriakidou, Laboratory of Medical Biology - Genetics, Faculty of Medicine, School of Health Sciences, Aristotle University, 54124, Thessaloniki, Greece. Tel: +30 2310999013, Email: chatzikyra@auth.gr
page: 33

INTRODUCTION

Parathyroid hormone (PTH) acts as an important regulator of calcium homeostasis in the human body [1]. The importance of PTH is reflected by the wide range of functions that calcium performs, as it participates in cell signaling, neural and muscular function, hormone release and regulation, and bone metabolism [2]. PTH increases the reabsorption of calcium in the kidney and the gastro- intestinal tract while at the same time enhances the release of calcium from the bone reservoir by indirectly stimulat- ing osteoclasts. Finally, PTH stimulates the conversion of 25-hydroxy vitamin D into 1,25-dihydroxy vitamin D (calcitriol), which is the active form of vitamin D and is released into the circulation [1]. Primary hyperparathyroidism (PHPT) is a prevalent endocrine disorder distinguished by the independent secre- tion of PTH as a result of overactivation of the parathyroid glands [3]. It is the third most common endocrine disorder after diabetes and thyroid disease, with prevalence between 0.1-0.4%. The number of diagnoses increases with age, peaking at 50-60 years, and it is more likely to occur in females. For the time being, PHPT is diagnosed by abnor- malities in PTH and blood calcium levels [4]. Almost 90% of the patients with PHPT are found to have sporadic, non-familial, and non-syndromic disease. Sporadic PHPT is usually caused by a single gland adeno- ma (85%) but may also be caused by hyperplasia of all four glands (10%). Double adenomas (2-5%) and parathyroid carcinomas (<1%) account for the least common causes of the disease. Several genes and pathways have been implicated in PHPT. These include genes involved in cell cycle regulation, Wnt/β-catenin signaling pathway, cellular growth, proliferation, tissue repairing, homeostasis, and apoptosis [5]. However, the genetic basis of PHPT is still under investigation. In the present study, four genes previously reported to be involved in parathyroid adenomas or PTH signa ling were analyzed for their association with PHPT. These genes are Annexin A2 (ANXA2), Mediator Complex Subu- nit 12 (MED12), Calmodulin 1 (CALM1), and Mitogen- Activated Protein Kinase 1 (MAPK1). The ANXA2 gene (15q22.2) encodes the ANXA2 pro- tein, a calcium-regulated phospholipid-binding protein that has been found upregulated in some tumor cells, affecting cell survival and mediating interactions between intercel- lular and extracellular microenvironments. It performs cru- cial roles in tumor progression, especially in the invasion and metastasis of tumor cells [6]. In addition, increased expression of ANXA2 has been reported in parathyroid adenomas [7, 8]. The MED12 gene (Xq13.1) is involved in gene regu- lation, as it serves as an essential component of the tran- scription mechanism of RNA polymerase II [9]. In general, MED12 variants are common in neoplasms and benign tumors, while upregulation of MED12 has been observed in parathyroid adenomas [10,11]. CALM1 (14q32.11) encodes one of the three calmo- dulin proteins, which are small calcium-sensitive proteins that rapidly transmit information about changes in calcium concentration, regulating gene expression in neurons and potentially shaping cardiac action in heart cells [12]. In parathyroid adenomas, calmodulin has been reported to inhibit PTH secretion [13]. Finally, the MAPK1 gene (22q11.22) encodes a mem- ber of the MAP protein kinase family. It is also known as extracellular signal-regulated kinase 2 (ERK2) and has been strongly associated with proliferation, differentiation, and signaling regulation in osteoblasts [14]. The MAPK1/ ERK2 protein is a key component of the Ras-Raf-MEK- ERK and c-Jun N-terminal kinases (JNK) signaling path- ways, which are downstream targets of PTH [14,15]. All these genes may have a role in PHPT predispo- sition due to their involvement in tumorigenesis in para- thyroid glands and PTH signaling pathways. No studies were reported to test the association of genetic variants of ANXA2, MED12, CALM1, and MAPK1 genes with PHPT predisposition, which is the reason why this pilot study was conducted. Genetic variants in ANXA2 (rs7170178 A>G, rs17191344 A>G, and rs11633032 G>A; all down- stream of the gene), MED12 (rs1057519912; exonic: C>G, T), CALM1 (rs12885713; intronic: C>T), and MAPK1 (rs1057519911, exonic; C>T), previously described as variants with clinical relevance in several diseases, were studied as predisposing factors to PHPT pathogenesis.

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