Dirk J Lefeber

Dirk J Lefeber
Radboud University | RU · Department of Neurology

About

173
Publications
22,302
Reads
How we measure 'reads'
A 'read' is counted each time someone views a publication summary (such as the title, abstract, and list of authors), clicks on a figure, or views or downloads the full-text. Learn more
5,215
Citations

Publications

Publications (173)
Preprint
The human plasma glycoproteome holds enormous potential to identify personalized biomarkers to diagnose and understand disease. Recent advances in mass spectrometry and software development are opening novel avenues to mine the glycoproteome for protein- and site-specific glycosylation changes. Here, we describe a novel plasma N-glycoproteomics met...
Article
Full-text available
Messenger RNA (mRNA) has emerged as a novel therapeutic approach for inborn errors of metabolism. Classic galactosemia (CG) is an inborn error of galactose metabolism caused by a severe deficiency of galactose‐1‐phosphate:uridylyltransferase (GALT) activity leading to neonatal illness and chronic impairments affecting the brain and female gonads. I...
Article
Full-text available
Congenital disorders of glycosylation (CDG) are inherited metabolic diseases characterized by mutations in enzymes involved in different steps of protein glycosylation, leading to aberrant synthesis, attachment or processing of glycans. Recently, immunological dysfunctions in several CDG types have been increasingly documented. Despite these observ...
Preprint
Full-text available
We used next-generation metabolic screening to identify new biomarkers for improved diagnosis and pathophysiological understanding of glucose transporter type 1 deficiency syndrome (GLUT1DS), comparing metabolic CSF profiles from 11 patients to those of 116 controls. This confirmed decreased CSF glucose and lactate levels in patients with GLUT1DS a...
Article
Full-text available
Ribitol-phosphate modification is crucial for the functional maturation of α-dystroglycan. Its dysfunction is associated with muscular dystrophy, cardiomyopathy, and central nervous system abnormalities; however, no effective treatments are currently available for diseases caused by ribitol-phosphate defects. In this study, we demonstrate that prod...
Article
Full-text available
Congenital Disorders of Glycosylation type 1 (CDG‐I) comprise a group of 27 genetic defects with heterogeneous multisystem phenotype, mostly presenting with non‐specific neurological symptoms. The biochemical hallmark of CDG‐I is a partial absence of complete N‐glycans on transferrin. However, recent findings of a diagnostic N‐tetrasaccharide for A...
Article
Synthetic sugar analogs are widely applied in metabolic oligosaccharide engineering (MOE) and as novel drugs to interfere with glycoconjugate biosynthesis. However, mechanistic insights on their exact cellular metabolism over time are mostly lacking. We combined ion-pair UHPLC-QqQ mass spectrometry using tributyl- and triethylamine buffers for sens...
Article
Full-text available
The sugar fucose is expressed on mammalian cell membranes as part of glycoconjugates and mediates essential physiological processes. The aberrant expression of fucosylated glycans has been linked to pathologies such as cancer, inflammation, infection, and genetic disorders. Tools to modulate fucose expression on living cells are needed to elucidate...
Article
Full-text available
PMM2-CDG is the most prevalent congenital disorder of glycosylation (CDG) with only symptomatic therapy. Some CDG have been successfully treated with D-galactose. We performed an open-label pilot trial with D-galactose in 9 PMM2-CDG patients. Overall, there was no significant improvement but some milder patients did show positive clinical changes;...
Article
Synthetic sugar analogs are widely applied in metabolic oligosaccharide engineering (MOE) and as novel drugs to interfere with glycoconjugate biosynthesis. However, mechanistic insights on their exact cellular metabolism over time are mostly lacking. We combined ion-pair UHPLC-QqQ mass spectrometry using tributyl- and triethylamine buffers for sens...
Article
Age-related macular degeneration (AMD) has been associated with protective genetic variants in the β1-3 glucosyltransferase (B3GLCT) locus through genome-wide association studies. B3GLCT mediates modification of proteins with thrombospondin type I repeats (TSR) that contain O-linked glucose β1-3 fucose and C-linked mannose glycosylation motifs. B3G...
Article
Full-text available
Background Recently, novel inborn errors of metabolism were identified due to mutations in V-ATPase assembly factors TMEM199 and CCDC115. Patients are characterized by generalized protein glycosylation defects, hypercholesterolemia and fatty liver disease. Here, we set out to characterize the lipid and fatty liver phenotype in human plasma, cell mo...
Article
Full-text available
Congenital disorders of glycosylation (CDGs) form a group of rare diseases characterized by hypoglycosylation. We here report the identification of 16 individuals from nine families who have either inherited or de novo heterozygous missense variants in STT3A, leading to an autosomal-dominant CDG. STT3A encodes the catalytic subunit of the STT3A-con...
Article
Full-text available
Fucosylation is essential for inter- and intracellular recognition, cell-cell interaction, fertilization and inflammatory processes. Only five types of congenital disorders of glycosylation (CDG) related to an impaired fucosylation have been described to date: FUT8-CDG, FCSK-CDG, POFUT1-CDG SLC35C1-CDG and the only recently described GFUS-CDG. This...
Article
Full-text available
Background In NANS deficiency, biallelic mutations in the N-acetylneuraminic acid synthase (NANS) gene impair the endogenous synthesis of sialic acid (N-acetylneuraminic acid) leading to accumulation of the precursor, N-acetyl mannosamine (ManNAc), and to a multisystemic disorder with intellectual disability. The aim of this study was to determine...
Article
Full-text available
Background: NANS-CDG is a recently described congenital disorder of glycosylation caused by biallelic genetic variants in NANS , encoding an essential enzyme in de novo sialic acid synthesis. Sialic acid at the end of glycoconjugates plays a key role in biological processes such as brain and skeletal development. Here, we present an observational c...
Article
Full-text available
EDEM3 encodes a protein that converts Man8GlcNAc2 isomer B to Man7-5GlcNAc2. It is involved in the endoplasmic reticulum-associated degradation pathway, responsible for the recognition of misfolded proteins that will be targeted and translocated to the cytosol and degraded by the proteasome. In this study, through a combination of exome sequencing...
Article
Full-text available
Bacterial pathogens such as Nontypeable Haemophilus influenzae (NTHi) can evade the immune system by taking up and presenting host-derived sialic acids. Herein, we report a detailed structure–activity relationship of sialic acid-based inhibitors that prevent the transfer of host sialic acids to NTHi. We report the synthesis and biological evaluatio...
Article
Galactose is an essential carbohydrate for cellular metabolism, as it contributes to energy production and storage in several human tissues while also being a precursor for glycosylation. Galactosylated glycoconjugates, such as glycoproteins, keratan sulfate-containing proteoglycans and glycolipids, exert a plethora of biological functions, includi...
Article
Behςet’s disease (BD) is an inflammatory disease mostly affecting men along the ancient silk route. In the present study we describe a Dutch family suffering from BD‐like disease with extreme pathergic responses, but without systemic inflammation. Genetic assessment revealed a combination of the HLA‐B*51 risk‐allele together with a rare heterozygou...
Article
Full-text available
Fucosylation of glycans impacts a myriad of physiological and pathological processes. Inhibition of fucose expression emerges as a potential therapeutic avenue for example in cancer, inflammation, and infection. In this study, we found that protected 2‐fluorofucose 1‐phosphate efficiently inhibits cellular fucosylation with a four to seven times hi...
Preprint
Fucosylation of glycans impacts a myriad of physiological and pathological processes. Inhibition of fucose expression emerges as a potential therapeutic avenue for example in cancer, inflammation, and infection. In this study, we found that protected 2-fluorofucose 1-phosphate efficiently inhibits cellular fucosylation with a four to seven times hi...
Preprint
a>Fucosylation of glycans impacts a myriad of physiological and pathological processes. Inhibition of fucose expression emerges as a potential therapeutic avenue for example in cancer, inflammation, and infection. In this study, we found that protected 2-fluorofucose 1-phosphate efficiently inhibits cellular fucosylation with a four to seven times...
Article
Full-text available
Protein N-glycosylation is a multifactorial process involved in many biological processes. A broad range of congenital disorders of glycosylation (CDGs) have been described that feature defects in protein N-glycan biosynthesis. Here, we present insights into the disrupted N-glycosylation of various CDG patients exhibiting defects in the transport o...
Preprint
Fucose sugars are expressed on mammalian cell membranes as part of glycoconjugates and mediates essential physiological processes. The aberrant expression of fucosylated glycans has been linked to pathologies such as cancer, inflammation, infection, and genetic disorders. Tools to modulate fucose expression on living cells are needed to elucidate t...
Preprint
Full-text available
Synthetic sugar analogs are widely applied in metabolic oligosaccharide engineering (MOE) and as novel drugs to interfere with glycoconjugate biosynthesis. However, mechanistic insights on their exact metabolism in the cell and over time are mostly lacking. We developed sensitive ion-pair UHPLC-QqQ mass spectrometry methodology for analysis of suga...
Article
Full-text available
Phosphoglucomutase 1 deficiency is a congenital disorder of glycosylation (CDG) with multiorgan involvement affecting carbohydrate metabolism, N-glycosylation and energy production. The metabolic management consists of dietary D-galactose supplementation that ameliorates hypoglycemia, hepatic dysfunction, endocrine anomalies and growth delay. Previ...
Article
Full-text available
Erratum for: Mutations in ATP6V1E1 or ATP6V1A Cause Autosomal-Recessive Cutis Laxa. Van Damme T, Gardeitchik T, Mohamed M, Guerrero-Castillo S, Freisinger P, Guillemyn B, Kariminejad A, Dalloyaux D, van Kraaij S, Lefeber DJ, Syx D, Steyaert W, De Rycke R, Hoischen A, Kamsteeg EJ, Wong SY, van Scherpenzeel M, Jamali P, Brandt U, Nijtmans L, Korenke...
Article
Full-text available
Glycosylation is an important post-translational modification for both intracellular and secreted proteins. For glycosylation to occur, cargo must be transported after synthesis through the different compartments of the Golgi apparatus where distinct monosaccharides are sequentially bound and trimmed, resulting in increasingly complex branched glyc...
Article
Full-text available
Congenital Disorders of Glycosylation (CDG) are a rapidly expanding group of rare genetic defects in glycosylation. In a novel CDG subgroup of Vacuolar‐ATPase assembly defects various degrees of hepatic injury have been described, including end stage liver disease. However, the CDG diagnostic workflow can be complex as liver disease per se may be a...
Article
Full-text available
Nucleotide sugars (NS) are fundamental molecules in life and play a key role in glycosylation reactions and signal conduction. Several pathways are involved in the synthesis of NS. The Leloir pathway, the main pathway for galactose metabolism, is crucial for production of uridine diphosphate (UDP)‐glucose and UDP‐galactose. The most common metaboli...
Article
Full-text available
In 2016, 11 male patients were reported with immunodeficiency and hepatic, gastric and (in some) neurological disease due to X‐linked ATP6AP1 deficiency (ATP6AP1‐CDG). In 2018, three other patients were reported with additional features: connective tissue abnormalities, sensorineural hearing loss, hyperopia, glomerular and tubular dysfunction, exoc...
Article
Variants in SLC35C1 underlie leucocyte adhesion deficiency (LADII) or congenital disorder of glycosylation type 2c (CDGIIc), an autosomal recessive disorder of fucosylation. This immunodeficiency syndrome is generally characterized by severe recurrent infections, Bombay blood group, reduced growth and intellectual disability (ID). Features are all...
Article
Background and aims: Vacuolar H+-ATP complex (V-ATPase) is a multisubunit protein complex required for acidification of intracellular compartments. At least five different factors are known to be essential for its assembly in the endoplasmic reticulum (ER). Genetic defects in four of these V-ATPase assembly factors show overlapping clinical featur...
Article
Full-text available
N-glycosylation of membrane receptors is important for a wide variety of cellular processes. In the immune system, loss or alteration of receptor glycosylation can affect pathogen recognition, cell-cell interaction, and activation as well as migration. This is not only due to aberrant folding of the receptor, but also to altered lateral mobility or...
Article
Full-text available
Intellectual disability (ID) is a neurodevelopmental condition that affects ~1% of the world population. In total 5−10% of ID cases are due to variants in genes located on the X chromosome. Recently, variants in OGT have been shown to co-segregate with X-linked intellectual disability (XLID) in multiple families. OGT encodes O-GlcNAc transferase (O...
Article
Full-text available
NGLY1 encodes the enzyme N‐glycanase that is involved in the degradation of glycoproteins as part of the endoplasmatic reticulum‐associated degradation pathway. Variants in this gene have been described to cause a multisystem disease characterized by neuromotor impairment, neuropathy, intellectual disability, and dysmorphic features. Here, we descr...
Article
Full-text available
Objective: The importance of protein glycosylation in regulating lipid metabolism is becoming increasingly apparent. We set out to further investigate this by studying the effects of defective glycosylation on plasma lipids in patients with B4GALT1-CDG, caused by a mutation in B4GALT1 with defective N-linked glycosylation. Approach: We studied p...
Article
Full-text available
Congenital disorders of glycosylation type I (CDG-I) are inborn errors of metabolism, generally characterized by multisystem clinical manifestations, including developmental delay, hepatopathy, hypotonia, and skin, skeletal, and neurological abnormalities. Among others, dolichol-phosphate-mannose (DPM) is the mannose donor for N-glycosylation as we...
Article
Background: Many muscular dystrophies currently remain untreatable. Recently, dietary ribitol has been suggested as a treatment for cytidine diphosphate (CDP)-l-ribitol pyrophosphorylase A (CRPPA, ISPD), fukutin (FKTN), and fukutin-related protein (FKRP) myopathy, by raising CDP-ribitol concentrations. Thus, to facilitate fast diagnosis, treatment...
Article
Review of the analytical and clinical validity as well as of the clinical utility of DNA-based testing for mutations in PGM3 in diagnostic, predictive and prenatal settings, and for risk assessment in relatives.
Article
Background: The importance of protein glycosylation in regulating lipid metabolism is increasingly becoming apparent. We set out to further investigate this by studying patients with type I congenital disorders of glycosylation (CDG-I) with defective N-glycosylation. Methods: We studied 29 patients of the two most prevalent types of CDG-I: ALG6-...
Article
Full-text available
Thrombocytopenia and platelet dysfunction are commonly observed in patients with dengue virus (DENV) infection and may contribute to complications such as bleeding and plasma leakage. The etiology of dengue-associated thrombocytopenia is multifactorial and includes increased platelet clearance. The binding of the coagulation protein von Willebrand...
Data
Platelet activation with impaired reactivity to TRAP in patients with acute dengue. Binding of fibrinogen to platelets and platelet P-selectin expression in unstimulated samples and after ex vivo stimulation with two concentrations of TRAP. (A, B) Data from Bandung cohort with longitudinal data from the different days of fever in dengue patients an...
Data
Flow cytometry gating strategy for determination of VWF binding to platelets. Platelets were gated based on forward and side scatter characteristics (A), followed by positivity for the platelet marker CD61-PC7 (B). The Median fluorescence intensity (MFI) of anti-VWF after stimulation (C) without agonist and (D) after ex vivo VWF-activation with ris...
Data
ADAMTS-13 activity in Bandung cohort. (A) Data from different days of fever in dengue patients and in healthy controls. Data are shown as geometric mean with 95% confidence interval. Differences between groups were analyzed using the Mann-Whitney U test. (B-D) The correlation between VWF binding to platelets without any agonist stimulation and plas...
Data
Differences in platelets and VWF parameters between dengue patients with and without bleeding, and patients with and without plasma leakage. Data shown are platelet numbers (A and B), VWF binding to platelets in the absence of an agonist (MFI) (C and D), Plasma VWF:Ag levels (E and F) and plasma active VWF levels (G and H). Differences between grou...
Data
Flow cytometry gating strategy for determination of sialic acid expression on platelets. Platelets were gated in P0 based on forward and side scatter characteristics (A) followed by positivity of the platelet marker CD61-PC7 in P1 (B). The median fluorescence intensity (MFI) of PE-labeled SNA lectin on platelets is determined from gate P1 (C, highe...
Data
Platelet desialylation is mediated by VWF binding to platelets. (A) Expression of Neuraminidase 1 (Neu-1) and binding of RCA lectin and VWF to platelets after incubation with two concentrations of DENV NS1 protein for 4 hrs at 37°C (n = 7 platelet donors). (B) Binding of VWF and RCA to platelets after incubating washed platelets with increasing con...
Data
Sialic acid expression and platelet reactivity in dengue patients with or without bleeding. Binding of the lectins (A) SNA and (B) MAL-II to platelet sialic acid residues were measured by flow cytometry in dengue patients with (n = 22) and without bleeding (n = 18). Platelet P-selectin expression and binding of fibrinogen to platelets in unstimulat...
Article
Full-text available
The Congenital Disorders of Glycosylation (CDG) are inborn errors of metabolism with a great genetic heterogeneity. Most CDG are caused by defects in the N‐glycan biosynthesis, leading to multisystem phenotypes. However, the occurrence of tissue‐restricted clinical symptoms in the various defects in dolichol‐phosphate‐mannose (DPM) synthesis remain...
Article
SLC35A2‐CDG is caused by mutations in the X‐linked SLC35A2 gene encoding the UDP‐galactose transporter. SLC35A2 mutations lead to hypogalactosylation of N‐glycans. SLC35A2‐CDG is characterized by severe neurological symptoms and, in many patients, early‐onset epileptic encephalopathy. In view of the diagnostic challenges, we studied the clinical, n...
Article
Over 100 human Congenital Disorders of Glycosylation (CDG) have been described. Of these, about 30% reside in the O-glycosylation pathway. O-glycosylation disorders are characterized by a high phenotypic variability, reflecting the large diversity of O-glycan structures. In contrast to N-glycosylation disorders, a generic biochemical screening test...
Article
Full-text available
Neuroblastoma cells highly express the disialoganglioside GD2, a tumor-associated carbohydrate antigen, which is only sparsely expressed on healthy tissue. GD2 is a primary target for the development of immunotherapy for neuroblastoma. Immunotherapy with monoclonal anti-GD2 antibodies has proven safety and efficacy in clinical trials and is include...
Chapter
Glycans have important functions in many biological processes such as the interaction of cells with their extracellular environment to mediate cell adhesion, macromolecular interactions, and pathogen invasion. Glycomics comprises the analyses of glycans, released from proteins and/or lipids in any biological sample and is complementary to genomics,...
Article
Full-text available
Sialic acids are important components of glycoproteins and glycolipids essential for cellular communication, infection, and metastasis. The importance of sialic acid biosynthesis in human physiology is well illustrated by the severe metabolic disorders in this pathway. However, the biological role of sialic acid catabolism in humans remains unclear...
Article
Full-text available
Genomics methodologies have significantly improved elucidation of Mendelian disorders. The combination with high-throughput functional-omics technologies potentiates the identification and confirmation of causative genetic variants, especially in singleton families of recessive inheritance. In a cohort of 99 individuals with abnormal Golgi glycosyl...
Article
Full-text available
Phosphoglucomutase 1 (PGM1) deficiency results in a mixed phenotype of a Glycogen Storage Disorder and a Congenital Disorder of Glycosylation (CDG). Screening for abnormal glycosylation has identified more than 40 patients, manifesting with a broad clinical and biochemical spectrum which complicates diagnosis. Together with the availability of D-ga...
Article
Full-text available
Clinical glycomics comprises a spectrum of different analytical methodologies to analyze glycan structures, which provides insights into the mechanisms of glycosylation. Within clinical diagnostics, glycomics serves as a functional readout of genetic variants, and can form a basis for therapy development, as was described for PGM1-CDG. Integration...
Article
Full-text available
Background: The phenotypic severity of congenital muscular dystrophy-dystroglycanopathy (MDDG) syndromes associated with aberrant glycosylation of α-dystroglycan ranges from the severe Walker-Warburg syndrome or muscle-eye-brain disease to mild, late-onset, isolated limb-girdle muscular dystrophy without neural involvement. However, muscular dystro...
Article
Full-text available
The survey summarizes in its first part the current status of knowledge on the Congenital Disorders of Glycosylation (CDG) with regard to their phenotypic spectrum, diagnostic and therapeutic strategies, and pathophysiology. It documents the clinical and basic research activities, and efforts to involve patients and their families. In the second pa...
Article
The neuron-restricted isoform 3 of the plasma membrane Ca(2+) ATPase plays a major role in the regulation of Ca(2+) homeostasis in the brain, where the precise control of Ca(2+) signaling is a necessity. Several function-affecting genetic mutations in the PMCA3 pump associated to X-linked congenital cerebellar ataxias have indeed been described. In...
Article
Objective: To describe the presentation and identify the cause of a new clinical phenotype, characterized by early severe neurodegeneration with myopathic and myasthenic features. Methods: This case study of 5 patients from 3 families includes clinical phenotype, serial MRI, electrophysiologic testing, muscle biopsy, and full autopsy. Genetic wo...
Article
Full-text available
We report on a 12-year-old adopted boy with psychomotor disability, absence seizures, and normal brain MRI. He showed increased (but initially, at 5 months, normal) serum cholesterol, increased alkaline phosphatases, transiently increased transaminases and hypoceruloplasminemia with normal serum and urinary copper. Blood levels of immunoglobulins,...