Mosaicism of the UDP-galactose transporter SLC35A2 causes a congenital disorder of glycosylation

Abstract

Biochemical analysis and whole-exome sequencing identified mutations in the Golgi-localized UDP-galactose transporter SLC35A2 that define an undiagnosed X-linked congenital disorder of glycosylation (CDG) in three unrelated families. Each mutation reduced UDP-galactose transport, leading to galactose-deficient glycoproteins. Two affected males were somatic mosaics, suggesting that a wild-type SLC35A2 allele may be required for survival. In infancy, the commonly used biomarker transferrin showed abnormal glycosylation, but its appearance became normal later in childhood, without any corresponding clinical improvement. This may indicate selection against cells carrying the mutant allele. To detect other individuals with such mutations, we suggest transferrin testing in infancy. Here, we report somatic mosaicism in CDG, and our work stresses the importance of combining both genetic and biochemical diagnoses.

Figure 1

Electrospray Ionization Mass Spectrometry Analyses of Whole Serum Tf from the Control Sample and Individual CDG-341 (A) Serum Tf from an unaffected control. (B) CDG-341 at 5 months of age showing loss of both galactose and sialic acid from multiple branches of complex type N-glycans. (C) CDG-341 at 38 months of age showing that Tf glycosylation has become normal.

Figure 2

Cell-Surface Analysis of Deficient Galactosylation and Increased Terminal β-GlcNAc and α-GalNAc (A) Flow cytometry analysis of Alexa-647-conjugated GSII (Griffonia simplicifolia) lectin in control and individual fibroblasts showing increased lectin binding in all three individuals. The parallel control is representative of three different lines that were tested. (B) Flow cytometry analysis of fluorescein-labeled VVA (Vicia Villosa) lectin in control and individual fibroblasts also showing increased binding in all three individuals. The parallel control is representative of three different lines that were tested.

Figure 3

SLC35A2 Transport Activity in Fibroblasts from Both Control and Affected Individuals Golgi transport of UDP [6-³H]-galactose in streptolysin-O permeabilized fibroblasts from controls and affected individuals. Each data point was done in duplicate, and error bars were calculated by SD.