Novel variants and clinical symptoms in four new ALG3‐CDG patients, review of the literature, and identification of AAGRP‐ALG3 as a novel ALG3 variant with alanine and glycine‐rich N‐terminus

• Published in: Human mutation Vol. 40; no. 7; pp. 938 - 951
• Main Authors: Himmelreich, Nastassja, Dimitrov, Bianca, Geiger, Virginia, Zielonka, Matthias, Hutter, Anna‐Marlen, Beedgen, Lars, Hüllen, Andreas, Breuer, Maximilian, Peters, Verena, Thiemann, Kai‐Christian, Hoffmann, Georg F., Sinning, Irmgard, Dupré, Thierry, Vuillaumier‐Barrot, Sandrine, Barrey, Catherine, Denecke, Jonas, Kölfen, Wolfgang, Düker, Gesche, Ganschow, Rainer, Lentze, Michael J., Moore, Stuart, Seta, Nathalie, Ziegler, Andreas, Thiel, Christian
• Format: Journal Article
• Language: English
• Published: United States Hindawi Limited 01.07.2019
• Subjects: AAGRP; Alanine; ALG3; Animals; Aorta; Cardiomyopathy; CDG‐I; Cells, Cultured; Child, Preschool; Chlorocebus aethiops; congenital disorders of glycosylation; Congenital Disorders of Glycosylation - genetics; COS Cells; Dolichol; Female; Glycine; Glycosylation; Hearing loss; Humans; hybrid protein; Infant; Literature reviews; Male; mannosyltransferase; Mannosyltransferases - genetics; Mutation; Open Reading Frames; Patients; Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase - deficiency; Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase - genetics; Polymorphism, Single Nucleotide; Transferrin; mannosyltransferase; ALG3; hybrid protein; CDG-I; AAGRP; congenital disorders of glycosylation
• ISSN: 1059-7794; 1098-1004
• DOI: 10.1002/humu.23764

ALG3‐CDG is one of the very rare types of congenital disorder of glycosylation (CDG) caused by variants in the ER‐mannosyltransferase ALG3. Here, we summarize the clinical, biochemical, and genetic data of four new ALG3‐CDG patients, who were identified by a type I pattern of serum transferrin and the accumulation of Man5GlcNAc2‐PP‐dolichol in LLO analysis. Additional clinical symptoms observed in our patients comprise sensorineural hearing loss, right‐descending aorta, obstructive cardiomyopathy, macroglossia, and muscular hypertonia. We add four new biochemically confirmed variants to the list of ALG3‐CDG inducing variants: c.350G>C (p.R117P), c.1263G>A (p.W421*), c.1037A>G (p.N346S), and the intron variant c.296+4A>G. Furthermore, in Patient 1 an additional open‐reading frame of 141 bp (AAGRP) in the coding region of ALG3 was identified. Additionally, we show that control cells synthesize, to a minor degree, a hybrid protein composed of the polypeptide AAGRP and ALG3 (AAGRP‐ALG3), while in Patient 1 expression of this hybrid protein is significantly increased due to the homozygous variant c.160_196del (g.165C>T). By reviewing the literature and combining our findings with previously published data, we further expand the knowledge of this rare glycosylation defect.