Impaired catabolism of free oligosaccharides due to MAN2C1 variants causes a neurodevelopmental disorder

• DOI: 10.1016/j.ajhg.2021.12.010
• Publication Date: 2022-01-18T15:38:12Z
• Authors: Nuno Maia; Sven Potelle; Hamide Yildirim; Sandrine Duvet; Shyam K. Akula; Celine Schulz; Elsa Wiame; Alexander Gheldof; Katherine O’Kane; Abbe Lai; Karen Sermon; Maïa Proisy; Philippe Loget; Tania Attié-Bitach; Chloé Quelin; Ana Maria Fortuna; Ana Rita Soares; Arjan P.M. de Bro...; Emile Van Schafti...; Marie-Cécile Nass...; Christopher A. Walsh; Katrien Stouffs; Paula Jorge; Anna C. Jansen; François Foulquier
• Keywords: Catabolism; Polymicrogyria; Cerebellar hypoplasia (non-human); Proband; Microcephaly

Free oligosaccharides (fOSs) are soluble oligosaccharide species generated during N-glycosylation of proteins. Although little is known about fOS metabolism, the recent identification NGLY1 deficiency, a congenital disorder deglycosylation (CDDG) caused by loss function an enzyme involved in has elicited increased interest processing. The catabolism fOSs been linked to activity specific cytosolic mannosidase, MAN2C1, which cleaves α1,2-, α1,3-, and α1,6-mannose residues. In this study, we report clinical, biochemical, molecular features six individuals, including two fetuses, with bi-allelic pathogenic variants MAN2C1; individuals from four different families. These exhibit dysmorphic facial features, anomalies such as tongue hamartoma, variable degrees intellectual disability, brain polymicrogyria, interhemispheric cysts, hypothalamic callosal anomalies, hypoplasia brainstem cerebellar vermis. Complementation experiments isogenic MAN2C1-KO HAP1 cells confirm pathogenicity three identified MAN2C1 variants. We further demonstrate that lead accumulation delay processing proband-derived cells. results emphasize involvement human neurodevelopmental disease importance catabolism.