{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMKRN3 is a maternally imprinted gene expressed exclusively from the paternal allele that plays a central inhibitory role in the timing of pubertal onset. Its expression in the hypothalamus is high during childhood and declines prior to puberty, thereby releasing the brake on gonadotropin-releasing hormone (GnRH) secretion. Multiple studies have demonstrated that loss‐of‐function mutations in MKRN3 represent the most common monogenic cause of familial central precocious puberty (CPP). In this capacity, MKRN3 normally restrains the activation of the hypothalamic–pituitary–gonadal axis, and disruptions in its function lead to premature sexual maturation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nInvestigations into MKRN3’s molecular function have revealed that it exerts its inhibitory effects at least in part by functioning as an E3 ubiquitin ligase. This enzymatic activity facilitates nonproteolytic ubiquitination of target substrates, such as poly(A)-binding proteins (PABPs), which in turn modulate mRNA stability and translation of key puberty regulators. In addition, MKRN3 represses the promoter activity of genes encoding stimulatory factors like KISS1 and TAC3, and interacts with molecules involved in RNA metabolism and chromatin regulation. Together, these actions underscore a complex mechanism whereby MKRN3 controls the transcriptional and post‐transcriptional switches essential for prepubertal repression of GnRH secretion."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nClinically, a broad spectrum of MKRN3 mutations—including frameshift, nonsense and missense variants—has been identified in patients with both familial and sporadic forms of CPP across diverse ethnic groups. Detailed mutation screening and longitudinal studies have established that reduced circulating levels of MKRN3 correlate with early pubertal activation. These findings have been instrumental in establishing MKRN3 as a diagnostic biomarker and as a potential target for understanding treatment outcomes with GnRH analogs. Moreover, recent work investigating the imprinting status of the gene has further confirmed its relevance in disorders such as Prader‐Willi syndrome, where disruptions of the 15q11‐13 imprinted locus may also affect pubertal development."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "40"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Nikolaos Settas, Catherine Dacou-Voutetakis, Maria Karantza, et al. 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