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

• Published in: American journal of human genetics 2022-02, Vol.109 (2), p.345-360
• Main Authors: Maia, Nuno, Potelle, Sven, Yildirim, Hamide, Duvet, Sandrine, Akula, Shyam K., Schulz, Celine, Wiame, Elsa, Gheldof, Alexander, O’Kane, Katherine, Lai, Abbe, Sermon, Karen, Proisy, Maïa, Loget, Philippe, Attié-Bitach, Tania, Quelin, Chloé, Fortuna, Ana Maria, Soares, Ana Rita, de Brouwer, Arjan P.M., Van Schaftingen, Emile, Nassogne, Marie-Cécile, Walsh, Christopher A., Stouffs, Katrien, Jorge, Paula, Jansen, Anna C., Foulquier, François
• Format: Article
• Language: English
• Subjects: Adolescent; Alleles; alpha-Mannosidase - deficiency; alpha-Mannosidase - genetics; Brain Stem - metabolism; Brain Stem - pathology; Cell Line, Tumor; Central Nervous System Cysts - genetics; Central Nervous System Cysts - metabolism; Central Nervous System Cysts - pathology; Cerebellar Vermis - metabolism; Cerebellar Vermis - pathology; Child; Child, Preschool; congenital disorder of deglycosylation; Congenital Disorders of Glycosylation - genetics; Congenital Disorders of Glycosylation - metabolism; Congenital Disorders of Glycosylation - pathology; Female; Fetus; free oligosaccharides; Glycosylation; Hamartoma - genetics; Hamartoma - metabolism; Hamartoma - pathology; Humans; Hypothalamus - metabolism; Hypothalamus - pathology; Intellectual Disability - genetics; Intellectual Disability - metabolism; Intellectual Disability - pathology; Leukocytes - metabolism; Leukocytes - pathology; Life Sciences; Male; MAN2C1; Mannose - metabolism; neurodevelopmental disorder; Oligosaccharides - metabolism; Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase - deficiency; Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase - genetics; Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase - metabolism; Polymicrogyria - genetics; Polymicrogyria - metabolism; Polymicrogyria - pathology; Tongue - metabolism; Tongue - pathology
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2021.12.010

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 α1,2-, α1,3-, and α1,6-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.