bims-meglyc 2023-10-22 papers

Orphanet J Rare Dis. 2023 Oct 19. 18(1): 329

Congenital disorders of glycosylation (CDG): state of the art in 2022.

Rita Francisco, Sandra Brasil, Joana Poejo, Jaak Jaeken, Carlota Pascoal, Paula A Videira, Vanessa Dos Reis Ferreira.

Congenital disorders of glycosylation (CDG) are a complex and heterogeneous family of rare metabolic diseases. With a clinical history that dates back over 40 years, it was the recent multi-omics advances that mainly contributed to the fast-paced and encouraging developments in the field. However, much remains to be understood, with targeted therapies' discovery and approval being the most urgent unmet need. In this paper, we present the 2022 state of the art of CDG, including glycosylation pathways, phenotypes, genotypes, inheritance patterns, biomarkers, disease models, and treatments. In light of our current knowledge, it is not always clear whether a specific disease should be classified as a CDG. This can create ambiguity among professionals leading to confusion and misguidance, consequently affecting the patients and their families. This review aims to provide the CDG community with a comprehensive overview of the recent progress made in this field.

Keywords: Congenital disorders of glycosylation (CDG); Disease classification; Nosology; Rare diseases

DOI: https://doi.org/10.1186/s13023-023-02879-z

Sci Rep. 2023 Oct 17. 13(1): 17648

Functional classification of DDOST variants of uncertain clinical significance in congenital disorders of glycosylation.

Sjors M Kas, Piyushkumar A Mundra, Duncan L Smith, Richard Marais.

Congenital disorders of glycosylation (CDG) are rare genetic disorders with a spectrum of clinical manifestations caused by abnormal N-glycosylation of secreted and cell surface proteins. Over 130 genes are implicated and next generation sequencing further identifies potential disease drivers in affected individuals. However, functional testing of these variants is challenging, making it difficult to distinguish pathogenic from non-pathogenic events. Using proximity labelling, we identified OST48 as a protein that transiently interacts with lysyl oxidase (LOX), a secreted enzyme that cross-links the fibrous extracellular matrix. OST48 is a non-catalytic component of the oligosaccharyltransferase (OST) complex, which transfers glycans to substrate proteins. OST48 is encoded by DDOST, and 43 variants of DDOST are described in CDG patients, of which 34 are classified as variants of uncertain clinical significance (VUS). We developed an assay based on LOX N-glycosylation that confirmed two previously characterised DDOST variants as pathogenic. Notably, 39 of the 41 remaining variants did not have impaired activity, but we demonstrated that p.S243F and p.E286del were functionally impaired, consistent with a role in driving CDG in those patients. Thus, we describe a rapid assay for functional testing of clinically relevant CDG variants to complement genome sequencing and support clinical diagnosis of affected individuals.

DOI: https://doi.org/10.1038/s41598-023-42178-y

PLoS One. 2023 ;18(10): e0292926

In depth characterization of midbrain organoids derived from wild type iPSC lines.

Ivan Pavlinov, Mitali Tambe, Joshua Abbott, Ha Nam Nguyen, Miao Xu, Manisha Pradhan, Atena Farkhondeh, Wei Zheng.

The ability to model human neurological tissues in vitro has been a major hurdle to effective drug development for neurological disorders. iPSC-derived brain organoids have emerged as a compelling solution to this problem as they have the potential to relevantly model the protein expression pattern and physiology of specific brain regions. Although many protocols now exist for the production of brain organoids, few attempts have been made to do an in-depth kinetic evaluation of expression of mature regiospecific markers of brain organoids. To address this, we differentiated midbrain-specific brain organoids from iPSC-lines derived from three apparently healthy individuals using a matrix-free, bioreactor method. We monitored the expression of midbrain-specific neuronal markers from 7 to 90-days using immunofluorescence and immunohistology. The organoids were further characterized using electron microscopy and RNA-seq. In addition to serving as a potential benchmark for the future evaluation of other differentiation protocols, the markers observed in this study can be useful as control parameters to identify and evaluate the disease phenotypes in midbrain organoid derived from patient iPSC-lines with genetic neurological disorders.

DOI: https://doi.org/10.1371/journal.pone.0292926