March 2024
March 8, 2024
The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders
Sidpra J, et al. Brain. , March 8, 2024
Inherited glycosylphosphatidylinositol deficiency disorders (IGDs) are a group of rare multisystem disorders arising from pathogenic variants in glycosylphosphatidylinositol anchor pathway (GPI-AP) genes. Despite associating 24 of at least 31 GPI-AP genes with human neurogenetic disease, prior reports are limited to single genes without consideration of the GPI-AP as a whole and with limited natural history data. In this multinational retrospective observational study, we systematically analyse the molecular spectrum, phenotypic characteristics, and natural history of 83 individuals from 75 unique families with IGDs, including 70 newly reported individuals: the largest single cohort to date.
READ MOREMarch 6, 2024
Exploring ligand interactions with human phosphomannomutases using recombinant bacterial thermal shift assay and biochemical validation
Monticelli M, Hay Mele B, Wright DM, Guerriero S, Andreotti G, Cubellis MV. Biochimie., March 6, 2024
PMM2-CDG, a disease caused by mutations in phosphomannomutase-2, is the most common congenital disorder of glycosylation. Yet, it still lacks a cure. Targeting phosphomannomutase-2 with pharmacological chaperones or inhibiting the phosphatase activity of phosphomannomutase-1 to enhance intracellular glucose-1,6-bisphosphate have been proposed as therapeutical approaches. We used Recombinant Bacterial Thermal Shift Assay to assess the binding of a substrate analog to phosphomannomutase-2 and the specific binding to phosphomannomutase-1 of an FDA-approved drug - clodronate. We also deepened the clodronate binding by enzyme activity assays and in silico docking. Our results confirmed the selective binding of clodronate to phosphomannomutase-1 and shed light on such binding.
READ MOREMarch 6, 2024
A rare case report of type 1 congenital disorders of glycosylation with acute decompensated heart failure and the incidental discovery of congenital disorders of glycosylation associated dilated cardiomyopathy and acute myocarditis
Yang WS, Grover S, Smith E, Selvanayagam JB. Eur Heart J Case Rep. , March 6, 2024
Congenital disorders of glycosylation (CDG) are rare genetically inherited defects leading to enzyme deficiency or malfunction in the glycosylation pathway. Normal glycosylation is essential to the development of normal cardiac anatomy and function. Congenital disorders of glycosylation-related cardiomyopathy are often the first manifestation detected in early life and may lead to sudden cardiac death. Approximately one-fifth of CDG types are related to cardiac diseases that include cardiomyopathy, rhythm disturbances, pericardial effusions, and structural heart disease. We report a rare case of a 26-year-old lady with CDG-1 who presented with acute-onset dyspnoea.
READ MOREMarch 4, 2024
Resilience in patients and family caregivers living with congenital disorders of glycosylation (CDG): a quantitative study using the brief resilience coping scale (BRCS)
Poejo J, Gomes AI, Granjo P, Dos Reis Ferreira V. Orphanet J Rare Dis, March 4, 2024
Patients and family caregivers living with Congenital Disorders of Glycosylation (CDG) experience a heavy burden, which can impact their resiliency and quality of life. The study's purpose was to measure the resilience levels of patients and family caregivers living with CDG using the brief resilience coping scale. We conducted an observational, cross-sectional study with 23 patients and 151 family caregivers living with CDG.
READ MOREMarch 1, 2024
Neural and metabolic dysregulation in PMM2-deficient human in vitro neural models
Radenkovic S, et al. Cell Rep. , March 1, 2024
Phosphomannomutase 2-congenital disorder of glycosylation (PMM2-CDG) is a rare inborn error of metabolism caused by deficiency of the PMM2 enzyme, which leads to impaired protein glycosylation. While the disorder presents with primarily neurological symptoms, there is limited knowledge about the specific brain-related changes caused by PMM2 deficiency. Here, we demonstrate aberrant neural activity in 2D neuronal networks from PMM2-CDG individuals.
READ MOREMarch 1, 2024
Motor improvement in children with PMM2-CDG syndrome following a six-month rehabilitation treatment utilising whole-body vibration; a retrospective study
Bossier C, Stark C, Martakis K, Duran I, Schoenau E. J Musculoskelet Neuronal Interact., March 1, 2024
The aim of this study was to assess the effect of a six-month interval rehabilitation treatment on motor function of children with PMM2-CDG syndrome (#212065 Congenital disorder of glycosylation, Type Ia; CDG1A, OMIM catalogue number).
READ MOREFebruary 2024
February 29, 2024
Reconstitution and resonance assignments of yeast OST subunit Ost4 and its critical mutant Ost4V23D in liposomes by solid-state NMR
Chaudhary BP, et al. J Biomol NMR., February 29, 2024
N-linked glycosylation is an essential and highly conserved co- and post-translational protein modification in all domains of life. In humans, genetic defects in N-linked glycosylation pathways result in metabolic diseases collectively called Congenital Disorders of Glycosylation. [...] In yeast, Ost4 is the smallest of nine subunits and bridges the interaction of the catalytic subunit, Stt3, with Ost3 (or its homolog, Ost6). Mutations of any C-terminal hydrophobic residues in Ost4 to a charged residue destabilizes the enzyme and negatively impacts its function. Specifically, the V23D mutation results in a temperature-sensitive phenotype in yeast. Here, we report the reconstitution of both purified recombinant Ost4 and Ost4V23D each in a POPC/POPE lipid bilayer and their resonance assignments using heteronuclear 2D and 3D solid-state NMR with magic-angle spinning.
READ MOREFebruary 26, 2024
Development of a Fluorescence and Quencher-based FRET Assay for Detection of Endogenous Peptide:N-glycanase/NGLY1 Activity
Hirayama H, et al. J Biol Chem., February 26, 2024
Cytosolic peptide:N-glycanase (PNGase/NGLY1 in mammals) catalyzes deglycosylation of N-glycans on glycoproteins. A genetic disorder caused by mutations in the NGLY1 gene leads to NGLY1 deficiency, with symptoms including motor deficits and neurological problems. Effective therapies have not been established, though a recent study used the administration of an adeno-associated viral vector expressing human NGLY1 to dramatically rescue motor functions in young Ngly1-/- rats. Thus, early therapeutic intervention may improve symptoms arising from central nervous system dysfunction, and assay methods for measuring NGLY1 activity in biological samples are critical for early diagnostics. In this study, we established an assay system for plate-based detection of endogenous NGLY1 activity using a FRET-based probe
READ MOREFebruary 24, 2024
Congenital disorder of glycosylation type Ia in a Chinese family: Function analysis of a novel PMM2 complex heterozygosis mutation
Zhong D, et al. Mol Genet Metab Rep., February 24, 2024
Congenital disorder of glycosylation type Ia (CDG-Ia) is an autosomal recessive genetic disease caused by a mutation in the phosphomannomutase 2 (PMM2) gene. We have identified a 13-month-old boy who has been diagnosed with CDG-Ia. He displays several characteristic symptoms, including cerebellar hypoplasia, severe developmental retardation, hypothyroidism, impaired liver function, and abnormal serum ferritin levels. Through whole-exome sequencing, we discovered novel complex heterozygous mutations in the PMM2 gene, specifically the c.663C > G (p.F221L) mutation and loss of exon 2.
READ MOREFebruary 5, 2024
Role of PIGM and PIGX in glycosylphosphatidylinositol biosynthesis and human health (Review)
Torres-Valdetano Á, Vallejo-Ruiz V, Milflores-Flores L, Martínez-Morales P. Biomed Rep, February 5, 2024
Glycosylphosphatidylinositol-glycan (GPI) is an anchor to specific cell surface proteins known as GPI-anchored proteins (APs) that are localized in lipid rafts and may act as cell co-receptors, enzymes and adhesion molecules. The present review investigated the significance of GPI biosynthesis class phosphatidylinositol-glycan (PIG)M and PIGX in GPI synthesis and their implications in human health conditions.
READ MORE