%0 Case Reports
%T 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.
%A Himmelreich N
%A Dimitrov B
%A Geiger V
%A Zielonka M
%A Hutter AM
%A Beedgen L
%A Hüllen A
%A Breuer M
%A Peters V
%A Thiemann KC
%A Hoffmann GF
%A Sinning I
%A Dupré T
%A Vuillaumier-Barrot S
%A Barrey C
%A Denecke J
%A Kölfen W
%A Düker G
%A Ganschow R
%A Lentze MJ
%A Moore S
%A Seta N
%A Ziegler A
%A Thiel C
%J Hum Mutat
%V 40
%N 7
%D 07 2019
%M 31067009
%F 4.7
%R 10.1002/humu.23764
%X 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 Man5 GlcNAc2 -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.