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.

Novel genetic causes for cerebral visual impairment

“…28,32,33 Variants in SLC35A2 lead to CDG type 2m, featured by ID, epilepsy, facial dysmorphisms, and transient abnormalities in transferin testing. [34][35][36] In the seven reported patients with CDG type 2m, CVI has not been mentioned, but other features, including the facial dysmorphism, epilepsy and severe ID were present in patient 6. The third glycosylation gene in which a variant was identified, PGAP1 (patient 12, reported elsewhere), is important in the GPI-anchor synthesis pathway.…”

Classical Galactosaemia and CDG, the N-Glycosylation Interface. A Review

“…This disorder leads to galactose-deficient glycoproteins as measured by N-glycans from whole serum using MALDI-TOF. This showed increased levels of hypogalactosylated glycans, particularly biantennary species (Ng et al 2013). Interestingly, in 3 affected children, the neonatal profile improved and normalized during the first few years of life.…”

“…At least four subtypes of CDG have been treated with dietary modulation of sugars: MPI-CDG, SLC55C1-CDG, PGM1-CDG (Hendriksz et al 2001;Harms et al 2002;Penel-Capelle et al 2003;de Lonlay and Seta 2009) and SLC35A2-CDG (Ng et al 2013;Dorre et al 2015).…”

Golgi post‐translational modifications and associated diseases

“…Similarly, defects in SLC35A2, an X-linked disorder, affect the UDP-galactose transporter. The patients also present intellectual disabilities and seizures and in some cases, ocular and skeletal abnormalities (Ng et al 2013). Recently, defects in SLC35A3, the main UDP-N-acetylglucosamine transporter, have been linked to a syndrome characterized by arthrogryposis, mental retardation, and seizures (AMRS) (Edvardson et al 2013).…”