Structure–Function Relationships of the CMP-Sialic Acid Transporter through Analysis of a Pathogenic Variant in an Alternatively Spliced Functional Isoform

The human CMP-sialic acid transporter (hCST) is a mammalian highly conserved type III antiporter that translocates CMP-sialic acid into the Golgi lumen, supporting sialylation. Although different works have focused on elucidating structure–function relationships in the hCST, this is the first study to address them in an alternatively spliced isoform. We have previously reported the expression of a functional human del177 isoform that has skipping of exon 6, resulting in a loss of 59 amino acids, without change in the open reading frame and conserving its C-terminal region. To elucidate structure–function relationships, we interrogated this isoform with a known pathogenic variant c.303C>T (p.Q101H) for the wt isoform, showing that its pathogenicity is significatively reduced in the mutated del177 isoform (del177Q101H). This is further explained by using a homology model based on previously reported mouse and maize crystal structures.