Structure-Function Relationships of the CMP-Sialic Acid Transporter through Analysis of a Pathogenic Variant in an...

Area of Science:

• Biochemistry
• Molecular Biology
• Genetics

Background:

• The human CMP-sialic acid transporter (hCST) is crucial for transporting CMP-sialic acid into the Golgi, supporting cellular sialylation.
• Previous research has explored hCST structure-function relationships, but not in alternatively spliced isoforms.

Purpose of the Study:

• To investigate the structure-function relationships of a previously identified functional human hCST del177 isoform, which lacks exon 6.
• To assess the pathogenicity of a known hCST variant (c.303C>T, p.Q101H) in the context of this del177 isoform.

Main Methods:

• Utilized a functional human del177 hCST isoform, characterized by the skipping of exon 6.
• Interrogated the del177 isoform with the pathogenic variant c.303C>T (p.Q101H).
• Employed homology modeling based on existing mouse and maize hCST crystal structures.

Main Results:

• The pathogenicity of the c.303C>T (p.Q101H) variant was significantly reduced in the del177 isoform compared to the wild-type (wt) hCST.
• Homology modeling provided insights into the structural basis for the altered pathogenicity in the del177 isoform.

Conclusions:

• Alternative splicing of hCST, specifically the del177 isoform, can modulate the functional impact of pathogenic variants.
• This study provides novel insights into hCST structure-function relationships and the implications of alternative splicing for transporter activity and disease.