{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n BNC2 (basonuclin 2) is an evolutionarily conserved zinc‐finger protein that functions as a transcriptional regulator with pleiotropic roles in development, tissue homeostasis, and disease. Several genetic studies have implicated regulatory variants in the BNC2 locus in modulating human pigmentation—both in the formation of facial pigmented spots and in determining skin color saturation—through enhancer‐mediated control of BNC2 expression in melanocytes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": " In addition, genome‐wide association and fine‐mapping studies in adolescent idiopathic scoliosis have identified variants within BNC2 that not only confer susceptibility but also correlate with curve severity, suggesting that aberrant or increased BNC2 expression influences spinal development."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "9"}]}, {"type": "t", "text": " In the context of cancer, the BNC2 locus at 9p22 has emerged repeatedly; candidate variants upstream of BNC2 are associated with ovarian cancer susceptibility"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "and"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ", and deletions or reduced expression of BNC2 have been documented in esophageal adenocarcinoma and hepatocellular carcinoma, consistent with tumor‐suppressive functions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "15"}]}, {"type": "t", "text": " Moreover, BNC2 has been linked to metabolic as well as cardiometabolic phenotypes, with associations noted in studies of glycemic control and via microRNA‐mediated regulation affecting several cardiometabolic pathways."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "18"}]}, {"type": "t", "text": " Foundational studies characterizing the BNC2 gene itself have revealed that, like its paralog BNC1, it encodes a nuclear protein capable of binding DNA (including rRNA gene promoters) and is widely expressed—with particularly high levels in testis, kidney, uterus, and intestine—suggesting diverse roles in gene regulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": " Finally, evidence from murine models demonstrates that BNC2 is indispensable in developmental processes such as craniofacial morphogenesis and hair follicle regeneration; notably, replacement of BNC2 with BNC1 fails to compensate, resulting in neonatal lethality and craniofacial abnormalities."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": " Collectively, these findings underscore that BNC2 functions as a multifaceted regulator whose precise expression is critical for normal pigmentation, skeletal, and epithelial development, and whose disruption can contribute to oncogenesis and other complex diseases."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}, {"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Nicholas Eriksson, J Michael Macpherson, Joyce Y Tung, et al. 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