{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nFAM126A, also known as hyccin or HYCC1, is a membrane protein that plays a critical role in myelin formation and maintenance. It functions as an intrinsic component of the plasma membrane phosphatidylinositol 4‐kinase complex—composed of PI4KIIIα and adaptor proteins such as TTC7 and EFR3—to regulate the synthesis of phosphatidylinositol 4‐phosphate (PtdIns(4)P). The generation of this lipid is essential for establishing plasma membrane identity and supporting the massive membrane expansion required in myelinating cells. Reduced PtdIns(4)P production resulting from FAM126A deficiency has been directly linked to the pathogenesis of hypomyelination and congenital cataract (HCC), a leukodystrophy characterized by central and peripheral myelin deficits and early-onset cataracts."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMutations in FAM126A—including deletions, splice-site changes, and missense variants—compromise the normal function of hyccin. Several studies have demonstrated that mutations can lead to protein deficiency or misfolding, with some missense changes prompting hyccin to aggregate in intracellular compartments such as the endoplasmic reticulum. This aberrant localization is thought to trigger kinase activities associated with the unfolded protein response, thereby exacerbating cellular stress. Clinically, the degree of residual protein function appears to influence the severity of the HCC phenotype, ranging from classical presentations with severe myelin deficiency and congenital cataract to milder forms with limited peripheral nerve involvement."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its indispensable role in myelination, hyccin is emerging as a key player in other aspects of neuronal function. In Drosophila models, modulation of the hyccin-containing PI4K complex has been shown to influence neuronal amyloid‑β accumulation, synaptic function, and motor behavior—findings that extend hyccin’s impact to neurodegenerative processes, including those relevant to Alzheimer’s disease. These results suggest that the proper regulation of plasma membrane phosphoinositide levels by hyccin is crucial not only for myelin maintenance but also for broader aspects of neuronal integrity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMoreover, recent evidence points to additional regulatory roles for the FAM126A gene product in non‐neuronal contexts. A circular RNA isoform derived from FAM126A, termed circFAM126A, has been implicated in non‑small cell lung cancer. This circRNA functions as a molecular sponge for miR‑613, thereby modulating the expression of IRS2 and affecting cell proliferation, migration, invasion, apoptosis, and cell cycle progression. Such findings underscore the multifaceted biological implications of FAM126A and hint at its potential contributions to diverse pathologies beyond congenital hypomyelinating disorders."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jeremy M Baskin, Xudong Wu, Romain Christiano, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The leukodystrophy protein FAM126A (hyccin) regulates PtdIns(4)P synthesis at the plasma membrane."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Cell Biol (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncb3271"}], "href": "https://doi.org/10.1038/ncb3271"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26571211"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26571211"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Federico Zara, Roberta Biancheri, Claudio Bruno, et al. 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