SLC35A2 – SLC35A2-congenital disorder of glycosylation

SLC35A2 encodes a UDP-galactose transporter responsible for importing UDP-galactose into the Golgi lumen for protein and lipid glycosylation. Pathogenic variants in SLC35A2 cause an X-linked glycosylation disorder (SLC35A2-CDG, MONDO:0010478) characterized by hypogalactosylation of N-glycans, severe neurodevelopmental impairment, and epileptic encephalopathy. To date, over 60 affected individuals have been reported, including sporadic de novo and mosaic cases in females and hemizygous males.

Genetic Evidence

Inheritance follows an X-linked dominant pattern with pathogenic SLC35A2 alleles arising de novo or via somatic mosaicism in females. A multicenter cohort study described 15 unrelated patients (11 females, 4 males) with nine novel variants and a total of 15 missense and ten loss-of-function alleles in SLC35A2 (PMID:30746764). Four additional patients from unrelated Han Chinese families carried one splice-site (c.426+1G>A), one large deletion (c.-322_c.274+1del), and two frameshift (c.781delC (p.Arg289ValfsTer88), c.601delG (p.Ala201GlnfsTer148)) variants (PMID:34122512). The recurrent missense variant c.991G>A (p.Val331Ile) has been observed in both mosaic and nonmosaic cases (PMID:29907092).

Functional Evidence

In vitro complementation assays in UDP-galactose transporter–deficient MDCK and CHO cells demonstrated loss of transporter activity for key missense and frameshift variants, confirming haploinsufficiency as the mechanism (PMID:30834435). Structure–function analyses identified critical transmembrane residues for UDP-galactose translocation, correlating with impaired glycan remodeling on patient serum transferrin. A human neuron stem cell model harboring loss-of-function alleles showed disrupted glycomic signatures, precocious neurodevelopment, and an excitatory/inhibitory imbalance in neural networks (PMID:39763953).

Animal Models and Somatic Mosaicism

Mosaic brain variants in SLC35A2 underlie mild malformations of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE), identified in 45% of pediatric MOGHE resections. A mouse model using mosaic in utero Slc35a2 knockout recapitulated cortical dysgenesis, increased epileptiform activity, and hyperactivity, confirming a causal role in neuronal migration defects and seizure susceptibility (PMID:39236911).

Clinical Spectrum and Diagnostics

Patients universally exhibit global developmental delay (HP:0001263), hypotonia (HP:0001252), and often early-onset epileptic seizures (HP:0001250) with hypsarrhythmia (HP:0002521) and cerebral atrophy on MRI (HP:0002059). Growth retardation and failure to thrive are common. Standard glycosylation screens may miss mosaic cases, making exome or targeted sequencing essential for diagnosis.

Integration and Take-Home

Extensive genetic and functional studies establish a strong association between SLC35A2 and SLC35A2-CDG, driven by loss-of-function and dominant-negative effects on UDP-galactose transport. Mouse and cellular models corroborate the neurodevelopmental and glycomic defects observed in patients. This evidence supports the clinical utility of genetic testing for early diagnosis, informed counseling, and potential galactose supplementation or targeted therapies.

References

• Journal of Inherited Metabolic Disease | 2019 | Clinical, neuroradiological, and biochemical features of SLC35A2-CDG patients PMID:30746764
• BMC Medical Genetics | 2018 | Mosaicism of the UDP-Galactose transporter SLC35A2 in a female causing a congenital disorder of glycosylation: a case report PMID:29907092
• Frontiers in Genetics | 2021 | Four New Cases of SLC35A2-CDG With Novel Mutations and Clinical Features PMID:34122512
• Glycobiology | 2019 | Functional analyses of the UDP-galactose transporter SLC35A2 using the binding of bacterial Shiga toxins as a novel activity assay PMID:30834435
• Neurobiology of Disease | 2024 | Slc35a2 mosaic knockout impacts cortical development, dendritic arborisation, and neuronal firing PMID:39236911

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