Structure–Function\nRelationships of the CMP-Sialic\nAcid Transporter through Analysis of a Pathogenic Variant in an Alternatively\nSpliced Functional Isoform

The human CMP-sialic acid transporter (hCST) is a mammalian\nhighly\nconserved type III antiporter that translocates CMP-sialic acid into\nthe Golgi lumen, supporting sialylation. Although different works\nhave focused on elucidating structure–function relationships\nin the hCST, this is the first study to address them in an alternatively\nspliced isoform. We have previously reported the expression of a functional\nhuman del177 isoform that has skipping of exon 6, resulting in a loss\nof 59 amino acids, without change in the open reading frame and conserving\nits C-terminal region. To elucidate structure–function relationships,\nwe interrogated this isoform with a known pathogenic variant c.303C>T\n(p.Q101H) for the <i>wt</i> isoform, showing that its pathogenicity\nis significatively reduced in the mutated del177 isoform (del177<sup>Q101H</sup>). This is further explained by using a homology model\nbased on previously reported mouse and maize crystal structures.