bims-meglyc 2023-09-17 papers

on Metabolic disorders affecting glycosylation

Issue of 2023‒09‒17
two papers selected by
Silvia Radenkovic, Frontiers in Congenital Disorders of Glycosylation Consortium

Biallelic missense variants in COG3 cause a congenital disorder of glycosylation with impairment of retrograde vesicular trafficking.
Single-cell brain organoid screening identifies developmental defects in autism.

J Inherit Metab Dis. 2023 Sep 15.

Biallelic missense variants in COG3 cause a congenital disorder of glycosylation with impairment of retrograde vesicular trafficking.

Ruizhi Duan, Dana Marafi, Zhi-Jie Xia, Bobby G Ng, Reza Maroofian, Farhana Taher Sumya, Ahmed K Saad, Haowei Du, Jawid M Fatih, Jill V Hunter, Hasnaa M Elbendary, Shahid M Baig, Uzma Abdullah, Zafar Ali, Stephanie Efthymiou, David Murphy, Tadahiro Mitani, Marjorie A Withers, Shalini N Jhangiani, Zeynep Coban-Akdemir, Daniel G Calame, Davut Pehlivan, Richard A Gibbs, Jennifer E Posey, Henry Houlden, Vladimir V Lupashin, Maha S Zaki, Hudson H Freeze, James R Lupski.

  Biallelic variants in genes for seven out of eight subunits of the conserved oligomeric Golgi complex (COG) are known to cause recessive congenital disorders of glycosylation (CDG) with variable clinical manifestations. COG3 encodes a constituent subunit of the COG complex that has not been associated with disease traits in human. Herein, we report two COG3 homozygous missense variants in four individuals from two unrelated consanguineous families that co-segregated with COG3-CDG. Clinical phenotypes of affected individuals include global developmental delay, severe intellectual disability, microcephaly, epilepsy, facial dysmorphism, and variable neurological findings. Biochemical analysis of serum transferrin from one family showed the loss of a single sialic acid. Western blotting on patient-derived fibroblasts revealed reduced COG3 and COG4. Further experiments showed delayed retrograde vesicular recycling in patient cells. This report adds to the knowledge of the COG-CDG network by providing collective evidence for a COG3-CDG rare disease trait and implicating a likely pathology of the disorder as the perturbation of GA trafficking. This article is protected by copyright. All rights reserved.

Keywords:  AOH/ROH analysis; Congenital disorders of glycosylation (CDG); Conserved oligomeric Golgi complex (COG); Family-based genomic analysis; Retrograde vesicular transport

DOI:  https://doi.org/10.1002/jimd.12679
Nature. 2023 Sep;621(7978): 373-380

Single-cell brain organoid screening identifies developmental defects in autism.

Chong Li, Jonas Simon Fleck, Catarina Martins-Costa, Thomas R Burkard, Jan Themann, Marlene Stuempflen, Angela Maria Peer, Ábel Vertesy, Jamie B Littleboy, Christopher Esk, Ulrich Elling, Gregor Kasprian, Nina S Corsini, Barbara Treutlein, Juergen A Knoblich.

The development of the human brain involves unique processes (not observed in many other species) that can contribute to neurodevelopmental disorders1-4. Cerebral organoids enable the study of neurodevelopmental disorders in a human context. We have developed the CRISPR-human organoids-single-cell RNA sequencing (CHOOSE) system, which uses verified pairs of guide RNAs, inducible CRISPR-Cas9-based genetic disruption and single-cell transcriptomics for pooled loss-of-function screening in mosaic organoids. Here we show that perturbation of 36 high-risk autism spectrum disorder genes related to transcriptional regulation uncovers their effects on cell fate determination. We find that dorsal intermediate progenitors, ventral progenitors and upper-layer excitatory neurons are among the most vulnerable cell types. We construct a developmental gene regulatory network of cerebral organoids from single-cell transcriptomes and chromatin modalities and identify autism spectrum disorder-associated and perturbation-enriched regulatory modules. Perturbing members of the BRG1/BRM-associated factor (BAF) chromatin remodelling complex leads to enrichment of ventral telencephalon progenitors. Specifically, mutating the BAF subunit ARID1B affects the fate transition of progenitors to oligodendrocyte and interneuron precursor cells, a phenotype that we confirmed in patient-specific induced pluripotent stem cell-derived organoids. Our study paves the way for high-throughput phenotypic characterization of disease susceptibility genes in organoid models with cell state, molecular pathway and gene regulatory network readouts.

DOI: https://doi.org/10.1038/s41586-023-06473-y