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 isoform, showing that its pathogenicity is significatively reduced in the mutated del177 isoform (del177). This is further explained by using a homology model based on previously reported mouse and maize crystal structures.