Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation

• Published in: American journal of human genetics Vol. 108; no. 7; pp. 1342 - 1349
• Main Authors: Polla, Daniel L., Edmondson, Andrew C., Duvet, Sandrine, March, Michael E., Sousa, Ana Berta, Lehman, Anna, Niyazov, Dmitriy, van Dijk, Fleur, Demirdas, Serwet, van Slegtenhorst, Marjon A., Kievit, Anneke J.A., Schulz, Celine, Armstrong, Linlea, Bi, Xin, Rader, Daniel J., Izumi, Kosuke, Zackai, Elaine H., de Franco, Elisa, Jorge, Paula, Huffels, Sophie C., Hommersom, Marina, Ellard, Sian, Lefeber, Dirk J., Santani, Avni, Hand, Nicholas J., van Bokhoven, Hans, He, Miao, de Brouwer, Arjan P.M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2021; Elsevier (Cell Press); Elsevier
• Subjects: Adolescent; Alleles; alpha-Mannosidase - deficiency; alpha-Mannosidase - genetics; Calcium-Binding Proteins - deficiency; Calcium-Binding Proteins - genetics; CDG; Cell Line; Child; Child, Preschool; Congenital Disorders of Glycosylation - blood; Congenital Disorders of Glycosylation - genetics; Developmental Disabilities - genetics; dysmorphism; EDEM3; Endoplasmic Reticulum - genetics; Female; Glycoproteins - blood; Glycosylation; high-mannose; Humans; Infant; Intellectual Disability - genetics; Life Sciences; Male; Mannosidase; mouse; Mutation; N-glycan; Pedigree; Polysaccharides - blood; Proteostasis Deficiencies - genetics; UPR; EDEM3; mouse; high-mannose; UPR; CDG; dysmorphism; N-glycan; Mannosidase
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2021.05.010

EDEM3 encodes a protein that converts Man8GlcNAc2 isomer B to Man7-5GlcNAc2. It is involved in the endoplasmic reticulum-associated degradation pathway, responsible for the recognition of misfolded proteins that will be targeted and translocated to the cytosol and degraded by the proteasome. In this study, through a combination of exome sequencing and gene matching, we have identified seven independent families with 11 individuals with bi-allelic protein-truncating variants and one individual with a compound heterozygous missense variant in EDEM3. The affected individuals present with an inherited congenital disorder of glycosylation (CDG) consisting of neurodevelopmental delay and variable facial dysmorphisms. Experiments in human fibroblast cell lines, human plasma, and mouse plasma and brain tissue demonstrated decreased trimming of Man8GlcNAc2 isomer B to Man7GlcNAc2, consistent with loss of EDEM3 enzymatic activity. In human cells, Man5GlcNAc2 to Man4GlcNAc2 conversion is also diminished with an increase of Glc1Man5GlcNAc2. Furthermore, analysis of the unfolded protein response showed a reduced increase in EIF2AK3 (PERK) expression upon stimulation with tunicamycin as compared to controls, suggesting an impaired unfolded protein response. The aberrant plasma N-glycan profile provides a quick, clinically available test for validating variants of uncertain significance that may be identified by molecular genetic testing. We propose to call this deficiency EDEM3-CDG.