Diep Taryn, Lipshutz Gerald S
Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.
Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Molecular Biology Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; Departments of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; Department of Psychiatry, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; Intellectual and Developmental Disabilities Research Center at UCLA, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; Semel Institute for Neuroscience, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
HGG Adv. 2025 Aug 7;6(4):100489. doi: 10.1016/j.xhgg.2025.100489.
Creatine phosphate is a high-energy molecule essential for the normal functioning of highly metabolically active organs and tissues. SLC6A8 encodes the only known creatine transporter in humans (CRT1); pathogenic variants result in a neurophenotype that includes intellectual disability, seizures, and autistic-like behaviors. Due to the importance of creatine phosphate in normal brain function, we compared the amino acid sequence among a group of terrestrial mammals and zebrafish. Finding high interspecies invariance, we (1) sought to quantitatively assess the effect of a number of existing disease-causing SLC6A8 variants on in vitro creatine uptake, comparing variant type/location, along with (2) the reported effect of missense variants on severity classification. Creatine uptake in the pathogenic variants studied demonstrated that the vast majority had a profound effect on uptake; only 1, in a peripheral extracellular loop, had a moderately reduced effect. Of the missense variant analysis, those occurring in C and N termini were tolerated more, while variants in transmembrane domains tended to more likely affect function. While the high degree of amino acid conservation across terrestrial mammals underscores its evolutionary importance, together with the variant analysis, these findings provide a framework for understanding genotype-phenotype correlations in variants of CRT1 and highlight the critical functional constraints.
磷酸肌酸是一种高能分子，对于高代谢活性器官和组织的正常功能至关重要。SLC6A8编码人类中唯一已知的肌酸转运蛋白（CRT1）；致病性变异会导致一种神经表型，包括智力残疾、癫痫发作和自闭症样行为。由于磷酸肌酸在正常脑功能中的重要性，我们比较了一组陆生哺乳动物和斑马鱼之间的氨基酸序列。发现种间高度不变性后，我们（1）试图定量评估一些现有的致病性SLC6A8变异对体外肌酸摄取的影响，比较变异类型/位置，以及（2）错义变异对严重程度分类的报道影响。对所研究的致病性变异的肌酸摄取表明，绝大多数变异对摄取有深远影响；只有一个位于外周细胞外环的变异对摄取的影响适度降低。在错义变异分析中，发生在C端和N端的变异更易被耐受，而跨膜结构域中的变异更有可能影响功能。虽然陆生哺乳动物之间高度的氨基酸保守性强调了其进化重要性，但结合变异分析，这些发现为理解CRT1变异中的基因型-表型相关性提供了一个框架，并突出了关键的功能限制。
