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

Abstract

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.

Congenital disorders of glycosylation and the challenge of rare diseases

“…Unlike the previous case, there is not a simple consistent link between the mutation and the final observed phenotype (i.e., altered glycosylation). In contrast to the classical presentation of a disease as seen in Himmelreich et al (), in the case of Ng et al (), we have a nonclassical or “occult” presentation of a disease where it is often difficult to demonstrate a difference in glycosylation. This nonclassical presentation had been observed previously in other studies of individuals carrying mutations in SLC35A2 and other types of CDG.…”

“…In summary, the studies of Himmelreich et al () and Ng et al () are excellent examples of the mainstream and challenging aspects of CDG research, respectively. The first question that arises is whether a mutation produces a biochemical defect and does this explain the phenotype on the whole organism level.…”

“…The two articles highlighted in this issue of Human Mutation demonstrate two instances in dealing with such rare diseases. The first (Himmelreich et al, ) is the “classical” approach. A patient presents with a severe phenotype and a biochemical test (determination of carbohydrate deficient transferrin [CDT] in serum) is done, suggesting a basis of the phenotype.…”

“…The first question that arises is whether a mutation produces a biochemical defect and does this explain the phenotype on the whole organism level. The study of Himmelreich et al () is an example of the direct linkage. This question becomes more difficult to answer when it is hard to observe the effect of biochemical defect at the level of the final product of the pathway (glycan structures).…”

ALG3-CDG: lethal phenotype and novel variants in Chinese siblings

“…They are mostly multisystem disorders often involving the central nervous system [2][3][4][5]. ALG3-CDG is a rare disorder, with only 23 patients reported so far [2][3][4][5][6][7][8][9][10][11][12][13]. ALG3 adds the 6th mannose to the growing dolichol-linked oligosaccharide in the ER [2,14].…”