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HGNC Approved Gene Symbol: CHGA
Cytogenetic location: 14q32.12 Genomic coordinates (GRCh38): 14:92,922,664-92,935,285 (from NCBI)
Chromogranin A (CHGA) regulates catecholamine storage and release through intracellular (vesiculogenic) and extracellular (catecholamine release--inhibitory) mechanisms (summary by Wen et al., 2004).
Kruggel et al. (1985) determined the N-terminal sequences of bovine and human adrenal medullary chromogranin A; the sequences are identical to each other and also to the published sequence of secretory protein I.
Deftos et al. (1986) cloned a cDNA for CHGA using mRNA from CHGA-producing medullary thyroid carcinoma cells in an expression vector, lambda gt11. Konecki et al. (1987) isolated a full-length clone encoding human chromogranin A from a lambda-gt10 cDNA library of a human pheochromocytoma. The nucleotide sequence showed that human chromogranin A is a 439-residue protein preceded by an 18-residue signal peptide. Sequence findings suggested that pancreastatin is derived from chromogranin A itself rather than from a protein that is only similar to chromogranin A. The pancreastatin sequence contained in human chromogranin A is flanked by sites for proteolytic processing. In man, pancreastatin may be important for the physiologic homeostasis of blood insulin levels as well as pathologic aberrations such as diabetes mellitus.
Wu et al. (1991) found that the chromogranin A gene has 8 exons and 7 introns spanning about 11 kb.
Murray et al. (1987) mapped CHGA to chromosome 14 by probing DNA from a hybrid cell panel with specific cDNA. Using a cDNA clone for the chromogranin A gene, Modi et al. (1989) mapped the gene to 14q32 by Southern blot analysis of human-rodent somatic cell hybrid DNAs and by in situ hybridization.
Simon-Chazottes et al. (1993) demonstrated that the chromogranin A gene is present in single dose in both the mouse and rat. Analysis of the allele distribution in an interspecific mouse backcross by single-strand conformation polymorphism positioned the Chga locus on mouse chromosome 12. By study of a rat/mouse somatic cell hybrid panel, they determined that the corresponding gene is on rat chromosome 6. In each case (mouse, rat, and human), chromogranin A is encoded in a conserved region with nearby markers, including the immunoglobulin heavy chain locus.
Chromogranin A is a protein costored and coreleased with catecholamines from storage granules in the adrenal medulla. Secretory protein I (parathyroid secretory protein; PSP) is a protein costored and coreleased with parathyroid hormone (PTH) from storage granules in the parathyroid gland. Like PTH (168450), its secretion is inversely proportional to extracellular calcium concentration. Bhargava et al. (1983) showed that the degree of phosphorylation of PSP is also inversely proportional to serum calcium, and that PSP is the major phosphorylated protein released by the parathyroid gland. Cohn et al. (1982) demonstrated a close similarity of these 2 proteins in amino acid composition, physical properties, and immunologic crossreactivity.
O'Connor and Deftos (1986) showed that chromogranin A is secreted by a great variety of peptide-producing endocrine neoplasms: pheochromocytoma, parathyroid adenoma, medullary thyroid carcinoma, carcinoids, oat-cell lung cancer, pancreatic islet-cell tumors, and aortic-body tumor.
Using immunohistochemistry on plastic sections, Cetin et al. (1993) investigated the occurrence and cellular distribution of CHGA, pancreastatin, and chromostatin (CST), a CHGA-derived bioactive peptide, in human endocrine pancreas of healthy and disease states and in the adrenal medulla. In the normal and diabetic pancreas, CST immunoreactivity was localized exclusively in beta cells, which were mostly unreactive for PST and CHGA. Both latter peptides were confined mainly to glucagon (alpha) cells. Insulinoma cells displayed strong insulin, PST, and CHGA immunoreactivities, but they were faintly immunoreactive for CST or unreactive. Adrenal chromaffin cells exhibited strong immunoreactivity for CHGA but lacked CST and PST immunoreactivities. Based on the peculiar distribution pattern of CST, PST, and CHGA, Cetin et al. (1993) suggested that CHGA is differentially processed in chromaffin and islet tissues and in insulinoma cells. The unique cellular localization of CST in the endocrine pancreas of normal and pathologic conditions may indicate that CST is involved in beta-cell function.
Kim et al. (2001) presented evidence that regulation of dense-core secretory granule biogenesis and hormone secretion in endocrine cells is dependent on CGA. Downregulation of CGA expression in a neuroendocrine cell line, PC12, by antisense RNAs led to profound loss of dense-core secretory granules, impairment of regulated secretion of a transfected prohormone, and reduction of secretory granule proteins. Transfection of bovine Cga into a CGA-deficient PC12 clone rescued the regulated secretory phenotype. Stable transfection of CGA into a CGA-deficient pituitary cell line, 6T3, which lacks a regulated secretory pathway, restored regulated secretion. Overexpression of CGA induced dense-core granules, immunoreactive for CGA, in nonendocrine fibroblast CV-1 cells. Kim et al. (2001) concluded that CGA is an 'on/off' switch that alone is sufficient to drive dense-core secretory granule biogenesis and hormone sequestration in endocrine cells.
Catestatin is a 21-amino acid neuroendocrine antimicrobial peptide fragment of CHGA that has effects on human autonomic function. It exhibits 3 naturally occurring polymorphisms: gly364 to ser (G364S), pro370 to leu (P370L), and arg374 to gln (R374Q). Aung et al. (2011) reported that catestatin and its variants all caused human mast cells and a human mast cell line to migrate, degranulate, and release leukotriene C4 (see 246530) and prostaglandins D2 (see 602598) and E2 (see 608152). The catestatins also increased intracellular Ca(2+) mobilization and induced production of proinflammatory cytokines/chemokines, including GMCSF (CSF2; 138960), CCL2 (158105), CCL3 (182283), and CCL4 (182284), which could be blocked by G protein, phospholipase C (see 172420), or ERK (see 601795) inhibitors. Inhibition of mast cell CHRNA7 (118511) did not affect catestatin-mediated activation of mast cells. Aung et al. (2011) concluded that catestatin may have immunomodulatory functions and link neuroendocrine and cutaneous immune systems.
Nobels et al. (1997) evaluated the clinical usefulness of chromogranin A, termed CgA by the authors, as a neuroendocrine serum marker. Serum levels of CgA, neuron-specific enolase (NSE), and the alpha-subunit of glycoprotein hormone (alpha-SU) were determined in 211 patients with neuroendocrine tumors and 180 control subjects with nonendocrine tumors. The concentrations of CgA, NSE, and alpha-SU were elevated in 50%, 43% and 24% of patients with neuroendocrine tumors, respectively. Serum CgA was most frequently increased in subjects with gastrinomas (100%), pheochromocytomas (89%), carcinoid tumors (80%), nonfunctioning tumors of the endocrine pancreas (69%), and medullary thyroid carcinomas (50%). The highest levels were observed in subjects with carcinoid tumors; NSE was most frequently elevated in patients with small cell lung carcinoma (74%) and alpha-SU was most frequently elevated in patients with carcinoid tumors (39%). A significant positive relationship was demonstrated between the tumor load and serum CgA levels (P less than 0.01, by X2 test). Elevated concentrations of CgA, NSE, and alpha-SU were present in, respectively, 7%, 35%, and 15% of control subjects. Markedly elevated serum levels of CgA, exceeding 300 mu-g/L, were observed in only 3 (2%) control patients compared to 76 (40%) patients with neuroendocrine tumors. The authors concluded that CgA was the best general neuroendocrine serum marker available at that time.
Granberg et al. (1999) measured CgA in 36 patients with type I multiple endocrine neoplasia (MEN1; 131100), of whom 9 lacked pancreatic involvement, 20 had biochemical evidence of pancreatic endocrine tumors, and 7 displayed radiologically detectable pancreatic tumors. CgA was also analyzed in 25 patients with sporadic pancreatic endocrine tumors, 39 subjects with inflammatory bowel disease, 7 patients harboring nonendocrine pancreatic disease, and 19 healthy controls. Of the MEN1 patients without pancreatic involvement, 4 of 9 (44%) had elevated CgA. Furthermore, 60% with biochemically unequivocal tumors and all with a radiologically visible tumor showed elevations. All 25 patients with sporadic pancreatic endocrine tumors had increased CgA, as did 28% of patients with inflammatory bowel disease and 57% with nonendocrine pancreatic disease. Granberg et al. (1999) concluded that nonendocrine diseases can cause elevations of CgA, and its spontaneous variation can be considerable. While plasma CgA is the most sensitive of the basal markers for neuroendocrine tumors, the authors felt that it could not replace other established measures when screening for early pancreatic involvement in MEN1.
Neurons and neuroendocrine cells contain membrane-delimited pools of peptide hormones, biogenic amines, and neurotransmitters with a characteristic electron-dense appearance on transmission electron microscopy. These vesicles, which are present throughout the neuroendocrine system and in a variety of neurons, store and release chromogranins and secretogranins (also known as granins), a unique group of acidic, soluble secretory proteins. The 3 'classic' granins are chromogranin A, which was first isolated from chromaffin cells of the adrenal medulla; chromogranin B (CHGB; 118920), initially characterized in a rat pheochromocytoma cell line; and chromogranin C (CHGC; 118930), also known as secretogranin II, which was originally described in the anterior pituitary. Taupenot et al. (2003) reviewed aspects of the structures, biochemical properties, and clinical importance of granins, with particular emphasis on chromogranin A. They made reference to 4 other acidic secretory proteins considered members of the granin family (Huttner et al., 1991): secretogranin III (Ottiger et al., 1990), secretogranin IV (Krisch et al., 1986), secretogranin V (SGNE1; 173120) (Mbikay et al., 2001), and secretogranin VI (GNAS; 139320) (Ischia et al., 1997).
Chromogranin A regulates catecholamine storage and release through intracellular (vesiculogenic) and extracellular (catecholamine release inhibitory) mechanisms. CHGA is a candidate gene for autonomic dysfunction syndromes, including intermediate phenotypes that contribute to hypertension. Wen et al. (2004) sequenced the CHGA gene in 180 ethnically diverse individuals with no history of renal failure and found a surprising pattern of CHGA variants that alter the expression and function of this gene, both in vivo and in vitro. Functional variants included both common alleles that qualitatively alter gene expression and rare alleles that qualitatively change the encoded product to alter the signaling potency of CHGA-derived catecholamine-release inhibitory catestatin peptides.
Mahapatra et al. (2005) generated Chga-null mice and observed decreased chromaffin granule size and number; elevated blood pressure; loss of diurnal blood pressure variation; increased left ventricular mass and cavity dimensions; decreased adrenal catecholamine, neuropeptide Y (NPY; 162640), and ATP contents; increased catecholamine/ATP ratio in the chromaffin granule; and increased plasma catecholamine and NPY levels. Return of elevated blood pressure to normal levels was achieved by either exogenous catestatin replacement or expression of a human CHGA transgene. Mahapatra et al. (2005) concluded that CHGA has a definitive role in autonomic control of the circulation.
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