Title :

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

Author(s) :

Maia, Nuno [Auteur]
Universidade do Minho = University of Minho [Braga]
Potelle, Sven [Auteur]
Yildirim, Hamide [Auteur]
Duvet, Sandrine [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Akula, Shyam K. [Auteur]
Schulz, Celine [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Wiame, Elsa [Auteur]
Gheldof, Alexander [Auteur]
O’Kane, Katherine [Auteur]
Lai, Abbe [Auteur]
Sermon, Karen [Auteur]
Proisy, Maïa [Auteur]
Loget, Philippe [Auteur]
Attié-Bitach, Tania [Auteur]
Quelin, Chloé [Auteur]
Fortuna, Ana Maria [Auteur]
Soares, Ana Rita [Auteur]
de Brouwer, Arjan P.M. [Auteur]
Van Schaftingen, Emile [Auteur]
Nassogne, Marie-Cécile [Auteur]
Walsh, Christopher A. [Auteur]
Stouffs, Katrien [Auteur]
Jorge, Paula [Auteur]
Jansen, Anna C. [Auteur]
Foulquier, Francois [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576

Journal title :

The American Journal of Human Genetics

Abbreviated title :

The American Journal of Human Genetics

Volume number :

109

Publisher :

Elsevier BV

Publication date :

2022-01

ISSN :

0002-9297

HAL domain(s) :

Sciences du Vivant [q-bio]

English abstract : [en]

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 ...
Show more >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.Show less >

Language :

Anglais

Peer reviewed article :

Non

Audience :

Internationale

Popular science :

Non

Administrative institution(s) :

Université de Lille
CNRS

Collections :

• Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576

Research team(s) :

Mécanismes moléculaires de la N-glycosylation et pathologies associées

Submission date :

2022-01-21T11:38:49Z
2022-01-24T11:19:54Z
2022-02-01T13:21:30Z