{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNeuronatin (NNAT) is an imprinted gene whose tightly regulated expression is critical for both normal development and diverse disease processes. Aberrant hypermethylation and consequent silencing of the NNAT locus in hematopoietic progenitor cells and leukemias underscore its potential involvement in epigenetic dysregulation during tumorigenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In pulmonary non‐small cell carcinoma, detectable NNAT expression hints at a contribution to tumor biology"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ", while studies in medulloblastoma reveal that co‐expression of NNAT splice forms enhances cell cycle progression, proliferation, and xenograft formation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " In the pituitary, loss of NNAT expression—accompanied by increased promoter methylation—supports a putative tumor‐suppressor role in adenoma development."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond these oncogenic contexts, NNAT plays key roles in metabolic and developmental regulation. In the hypothalamus, its expression is modulated by leptin—a relationship that links NNAT to appetite regulation and energy homeostasis, with implications for both childhood and adult obesity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " As a substrate of the ubiquitin ligase malin, NNAT is normally targeted for degradation; failure to do so leads to its accumulation and aberrant activation of glycogen synthase, a mechanism that contributes to the pathogenesis of Lafora disease."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Differential imprinting in pluripotent stem cells further underscores NNAT’s significance in developmental processes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " In glioblastoma multiforme, NNAT isoforms are enriched in tumor stem cell populations, with elevated levels correlating with increased proliferation and poorer patient survival."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Aberrant accumulation of NNAT in both cortical neurons and pancreatic β‐cells has been linked to cellular toxicity in Lafora disease, indicating a role in neurodegenerative and metabolic dysfunction."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " In Wilms tumor, hypomethylation of regulatory elements—particularly at regions containing CTCF binding sites—associates with NNAT overexpression, suggesting a mechanistic role in pediatric tumorigenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nNNAT also exerts important functions in non‐neuronal tissues. Its localization to the endoplasmic reticulum of keratinocytes and pancreatic β‐cells implicates NNAT in regulating intracellular Ca²⁺ levels and in modulating insulin secretion."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " In high‐grade soft tissue sarcomas, emerging evidence of aberrant DNA methylation patterns may reflect similar epigenetic mechanisms affecting NNAT expression"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "; furthermore, the intrinsic propensity of NNAT to misfold and form toxic aggregates has been directly implicated in the pathogenesis of both Lafora disease and diabetes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " In medullary thyroid cancer, NNAT expression levels vary with RET mutation patterns, supporting a potential tumor‐suppressive role in this endocrine malignancy."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, recent investigations have begun to unravel the role of NNAT in neuropsychiatric disorders and additional cancers. Preliminary whole‐exome studies in male individuals with anorexia nervosa are exploring NNAT among other candidate genes"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": ", while NNAT has been identified as a negative prognostic biomarker in breast cancer."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": " Moreover, rare-coding missense mutations in NNAT are associated with increased susceptibility to anorexia nervosa, likely by compromising its biochemical integrity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": " In hepatocellular carcinoma, altered methylation status of NNAT may drive disease progression"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": ", and in estrogen receptor–positive breast cancer, NNAT modulates intracellular Ca²⁺ homeostasis and endoplasmic reticulum function to influence cell proliferation and migration."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": " Finally, mutations that affect NNAT’s post-translational modification sites have been linked to the pathogenesis of anorexia nervosa, further underscoring its multifaceted role in neuropsychological disorders."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Steven J Kuerbitz, Joshua Pahys, Alison Wilson, et al. 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