{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSLC6A8 encodes a Na⁺/Cl⁻‐dependent creatine transporter that mediates the uptake of creatine into cells, thereby supplying a high‐energy phosphate reservoir essential for ATP buffering. This transporter plays a pivotal role in maintaining cellular energy homeostasis by facilitating creatine acquisition from both dietary sources and intercellular exchange, as well as by contributing to the re‐uptake of creatine at synapses to modulate neurotransmission in high–energy–demand tissues such as brain, muscle, and heart."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMutations in SLC6A8 underlie a spectrum of creatine transporter deficiency syndromes, which are among the most common causes of X‐linked intellectual disability. Affected individuals typically exhibit cerebral creatine depletion accompanied by developmental delay, speech impairment, seizures, and behavioral disturbances. Biochemical hallmarks of the disorder include an elevated urinary creatine/creatinine ratio and markedly reduced creatine uptake in patient–derived cells, indicating that diverse pathogenic variants impair transporter function through mechanisms such as misfolding, aberrant trafficking, or disruption of substrate binding."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "21"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, detailed structure–function studies and mutagenesis have delineated key residues and domains critical for substrate recognition and transporter kinetics. Regulatory mechanisms involving kinases such as SGK1/SGK3, and modulators including Klotho and regulatory kinases (SPAK/OSR1), have been shown to enhance the maximal transport capacity of SLC6A8, while alternative splicing and post–translational modifications (e.g., N–linked glycosylation) further influence its expression and function. These insights, supported by electrophysiological studies in heterologous systems and structural modeling, underscore the complex regulation of substrate affinity, transporter trafficking, and overall activity in both normal and pathogenic settings."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "22", "end_ref": "33"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its classical role in neural energy homeostasis, emerging evidence implicates SLC6A8 in diverse physiological and pathophysiological processes. Altered creatine transport has been observed in non–neuronal tissues including the intestine, kidney, and even in contexts such as hepatocellular carcinoma, suggesting broader biological implications. In addition, studies of alternative splice variants and investigations into the promoter activity of both SLC6A8 and its pseudogene highlight complex transcriptional regulation that may influence tissue–specific expression and therapeutic responsiveness. These findings, together with investigations into novel compounds such as cyclocreatine, open new avenues for targeted therapies in creatine deficiency and related disorders, while also prompting further exploration of creatine transport in cancer and other conditions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "34", "end_ref": "41"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Efraim H Rosenberg, Ligia S Almeida, Tjitske Kleefstra, et al. 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