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December 2024
December 10, 2024
Intron retention caused by a canonical splicing variant in SSR4-related congenital disorder of glycosylation
Wang Q, et al. J Hum Genet. , December 10, 2024
Congenital disorder of glycosylation type Iy (CDG-Iy) is an X-linked monogenic inherited disease caused by variants in the SSR4 gene. To date, a total of 11 variants have been identified in 14 CDG-Iy patients. Our study identified a novel canonical splicing variant, c.67+2T>C, in the SSR4 gene (according to the transcript NM_006280.3) in a Chinese CDG-Iy family. Functional analysis revealed that the c.67+2T>C variant induced the retention of the first 46 bp of intron 1 via the recognition of the downstream GC dinucleotide as a non-canonical cryptic donor splice site. This aberrant mRNA splicing resulted in the occurrence of a premature termination codon, triggered nonsense-mediated mRNA decay, and decreased the SSR4 gene expression.
READ MOREDecember 6, 2024
CHIME Syndrome in a Child With Homozygous PIGL p.Leu167Pro Variant
Arany ES, Zocche D, Mellerio JE, Holder-Espinasse M, Cobben J. Am J Med Genet A., December 6, 2024
CHIME syndrome is a variable condition characterized by ichthyosiform dermatosis, accompanied by intellectual disability, ocular colobomas, ear anomalies, and heart defects. It is an autosomal recessive condition caused by biallelic pathogenic variants in the PIGL gene. Until now, all reports of individuals affected with CHIME syndrome showed the PIGL c.500T>C p.Leu167Pro DNA variant on one allele of the PIGL gene, in combination with another PIGL DNA variant on the other allele. This has led to the hypothesis that the p.Leu167Pro variant determines to a mild phenotypic effect only and that the core phenotype is determined by the second PIGL DNA variant. We report the first individual with CHIME syndrome, a 6-year-old girl, with homozygous PIGL p.Leu167Pro variants, defusing this hypothesis as she is not mildly affected.
READ MOREDecember 5, 2024
Clinical severity and cardiac phenotype in phosphomannomutase 2-congenital disorders of glycosylation : Insights into genetics and management recommendations
Holubova V, et al. J Inherit Metab Dis., December 5, 2024
Cardiac involvement (CI) in phosphomannomutase 2-congenital disorders of glycosylation (PMM2-CDG) is part of the multisystemic presentation contributing to high mortality rates. The most common cardiac manifestations are pericardial effusion, cardiomyopathy, and structural heart defects. A genotype-phenotype correlation with organ involvement has not yet been described. We analyzed clinical, biochemical, and molecular genetic data of 222 patients from eight European centers and characterized the natural course of patients with CI.
READ MORENovember 2024
November 27, 2024
FUT8 Regulates Cerebellar Neurogenesis and Development Through Maintaining the Level of Neural Cell Adhesion Molecule Cntn2
Wei, K et al. Mol Neurobiol., November 27, 2024
Core fucosylation at N-glycans, which is uniquely catalyzed by fucosyltransferase FUT8, plays essential roles in post-translational regulation of protein function. Aberrant core fucosylation leads to neurological disorders in individuals with congenital glycosylation disorders (CDG). However, the underlying mechanisms for these neurological defects remain largely unknown. In this study, we have showed that FUT8 and fucosylation are abundant in cerebellum. Specific deletion of Fut8 in cerebellar granule neuron progenitors (GNPs) results in the impaired proliferation and differentiation of GNPs, as well as the compromised neuronal development, synaptic physiology and motor coordination. Mechanistically, we have showed that Fut8 deficiency reduced Contactin 2 (Cntn2) expression, a member of neural cell adhesion molecules (NCAMs).
READ MORENovember 26, 2024
Quantitative Assessment of Core Fucosylation for Congenital Disorders of Glycosylation
Wada Y, Kadoya M. Mass Spectrom., November 26, 2024
Congenital disorders of glycosylation (CDG) include a group of diseases characterized by defects of N-glycan fucosylation. The analytical molecule of choice for the diagnosis of CDG affecting N-glycosylation is serum transferrin: approximately 10% of the glycans attached to transferrin are fucosylated via an α1,6 linkage at the innermost N-acetylglucosamine residue, termed "core fucosylation." Isoelectric focusing (IEF) of transferrin is often used for diagnosis, but IEF is ineffective in detecting abnormal fucosylation. Here, we present mass spectrometry (MS) methods for detecting fucosylation disorders
READ MORENovember 20, 2024
Case series; NUS1 deletions cause a progressive myoclonic epilepsy with ataxia
Landais R, Strong J, Thomas RH. Seizure., November 20, 2024
Mutations in NUS1 cause a neurological congenital glycosylation disorder which encompasses a spectrum from developmental encephalopathy to musculoskeletal, hearing, and visual abnormalities. Pathogenic variants include both point mutations and genomic deletions. We report an adult phenotype of progressive myoclonus epilepsy (PME) and a review of cases with a complete or partial deletion of NUS1.
READ MORENovember 18, 2024
O-GlcNAcylation modulates expression and abundance of N-glycosylation machinery in an inherited glycosylation disorder
Matheny-Rabun C, et al. Cell Rep., November 18, 2024
Core components of the N-glycosylation pathway are known, but the metabolic and post-translational mechanisms regulating this pathway in normal and disease states remain elusive. Using a multi-omic approach in zebrafish, we discovered a mechanism whereby O-GlcNAcylation directly impacts the expression and abundance of two rate-limiting proteins in the N-linked glycosylation pathway. We show in a model of an inherited glycosylation disorder PMM2-CDG, congenital disorders of glycosylation that phosphomannomutase deficiency is associated with increased levels of UDP-GlcNAc and protein O-GlcNAcylation. O-GlcNAc modification increases the transcript and protein abundance of both NgBR and Dpagt1 in pmm2m/m mutants. Modulating O-GlcNAc levels, NgBR abundance, or Dpagt1 activity exacerbated the cartilage phenotypes in pmm2 mutants, suggesting that O-GlcNAc-mediated increases in the N-glycosylation machinery are protective.
READ MORENovember 12, 2024
Processing of N-glycans in the ER and Golgi influences the production of surface sialylated glycoRNA
Liu YS, et al. Glycoconj. J., November 12, 2024
Glycoconjugates, including glycans on proteins and lipids, have obtained significant attention due to their critical roles in both intracellular and intercellular biological functions and processes. Notably, recent discoveries have revealed the presence of glycosylated RNAs (glycoRNAs) on cell surfaces. Despite the well-characterized roles of RNA modifications, RNA glycosylation remains relatively unexplored. In this study, we investigate the relationship between N-glycosylation and RNA glycosylation. Using a recombinant Siglec11-Fc as a probe, we detected surface sialylated glycoRNAs in human cell lines and identified their dependency on the catalytic isoforms of the oligosaccharyltransferase (OST) complex, implicating STT3A-dependent protein glycosylation as a predominant contributor for affecting indirect generation of glycoRNAs.
READ MORENovember 9, 2024
PIGK defects induce apoptosis in Purkinje cells and acceleration of neuroectodermal differentiation
Chen, S, et al. Cell Death Dis . , November 9, 2024
allelic mutations in PIGK cause GPI biosynthesis defect 22 (GPIBD22), characterized with developmental delay, hypotonia, and cerebellar atrophy. The understanding of the underlying causes is limited due to the lack of suitable disease models. To address this gap, we generated a mouse model with PIGK deficits, specifically in Purkinje cells (Pcp2-cko) and an induced pluripotent stem cell (iPSC) model using the c.87dupT mutant (KI) found in GPIBD22 patients.
READ MORENovember 9, 2024
Non-targeted N-glycome profiling reveals multiple layers of organ-specific diversity in mice
Helm, J et al. Nature Communications., November 9, 2024
N-glycosylation is one of the most common protein modifications in eukaryotes, with immense importance at the molecular, cellular, and organismal level. Accurate and reliable N-glycan analysis is essential to obtain a systems-wide understanding of fundamental biological processes. Due to the structural complexity of glycans, their analysis is still highly challenging. Here we make publicly available a consistent N-glycome dataset of 20 different mouse tissues and demonstrate a multimodal data analysis workflow that allows for unprecedented depth and coverage of N-glycome features.
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