{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n FAM126A, also known as hyccin, is a membrane‐associated protein that plays a pivotal role in regulating phosphatidylinositol 4‐phosphate (PI4P) synthesis at the plasma membrane by serving as a key component of the PI4KIIIα complex, which also includes PI4KIIIα and its adaptors TTC7 and EFR3."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Studies in patients with hypomyelination and congenital cataract (HCC) have demonstrated that both complete loss‐of‐function mutations and specific missense mutations in FAM126A lead to destabilization of this complex, resulting in decreased PI4P levels that impair plasma membrane identity and myelin formation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " In the central and peripheral nervous systems, FAM126A is critical for proper myelination; its deficiency disrupts neuron–glia signaling necessary for initiating and maintaining the myelin sheath, thereby contributing to clinical manifestations such as congenital cataract, developmental delay, and peripheral neuropathy."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}, {"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Furthermore, biochemical and structural analyses suggest that FAM126A not only stabilizes the PI4KIIIα complex but also is essential for maintaining axonal sheath integrity in model systems, with restoration of function observed upon overexpression of either human FAM126A or its homolog FAM126B."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Additionally, studies in Drosophila models indicate that downregulating hyccin (FAM126A) leads to reduced neural deficits and lower neuronal amyloid‐β accumulation, further emphasizing its role in neuronal homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Collectively, these findings underscore that FAM126A is indispensable for the regulation of lipid kinase activity and myelin homeostasis, and that its dysfunction constitutes a central pathogenic mechanism in leukodystrophies such as HCC."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "3"}, {"type": "fg_f", "ref": "2"}, {"type": "fg_f", "ref": "5"}, {"type": "fg_f", "ref": "7"}, {"type": "fg_f", "ref": "6"}, {"type": "fg_f", "ref": "9"}, {"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jeremy M Baskin, Xudong Wu, Romain Christiano, et al. 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