Impaired catabolism of free oligosaccharides due to MAN2C1 variants causes a neurodevelopmental disorder
Résumé
Free oligosaccharides (fOSs) are soluble oligosaccharide species generated during N-glycosylation of proteins. Although little is known
about fOS metabolism, the recent identification of NGLY1 deficiency, a congenital disorder of deglycosylation (CDDG) caused by loss of
function of an enzyme involved in fOS metabolism, has elicited increased interest in fOS processing. The catabolism of fOSs has been
linked to the activity of a specific cytosolic mannosidase, MAN2C1, which cleaves a1,2-, a1,3-, and a1,6-mannose residues. In this study,
we report the clinical, biochemical, and molecular features of six individuals, including two fetuses, with bi-allelic pathogenic variants in
MAN2C1; the individuals are from four different families. These individuals exhibit dysmorphic facial features, congenital anomalies
such as tongue hamartoma, variable degrees of intellectual disability, and brain anomalies including polymicrogyria, interhemispheric
cysts, hypothalamic hamartoma, callosal anomalies, and hypoplasia of brainstem and cerebellar vermis. Complementation experiments
with isogenic MAN2C1-KO HAP1 cells confirm the pathogenicity of three of the identified MAN2C1 variants. We further demonstrate
that MAN2C1 variants lead to accumulation and delay in the processing of fOSs in proband-derived cells. These results emphasize the
involvement of MAN2C1 in human neurodevelopmental disease and the importance of fOS catabolism.