Bad Münster am Stein-Ebernburg, Germany
Bad Münster am Stein-Ebernburg, Germany

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Tegtmeyer L.C.,University of Munster | Rust S.,Leibniz Institute For Arterioskleroseforschung | Van Scherpenzeel M.,Radboud University Nijmegen | Ng B.G.,Sanford Burnham Institute for Medical Research | And 47 more authors.
New England Journal of Medicine | Year: 2014

BACKGROUND: Congenital disorders of glycosylation are genetic syndromes that result in impaired glycoprotein production. We evaluated patients who had a novel recessive disorder of glycosylation, with a range of clinical manifestations that included hepatopathy, bifid uvula, malignant hyperthermia, hypogonadotropic hypogonadism, growth retardation, hypoglycemia, myopathy, dilated cardiomyopathy, and cardiac arrest. METHODS: Homozygosity mapping followed by whole-exome sequencing was used to identify a mutation in the gene for phosphoglucomutase 1 (PGM1) in two siblings. Sequencing identified additional mutations in 15 other families. Phosphoglucomutase 1 enzyme activity was assayed on cell extracts. Analyses of glycosylation efficiency and quantitative studies of sugar metabolites were performed. Galactose supplementation in fibroblast cultures and dietary supplementation in the patients were studied to determine the effect on glycosylation. RESULTS: Phosphoglucomutase 1 enzyme activity was markedly diminished in all patients. Mass spectrometry of transferrin showed a loss of complete N-glycans and the presence of truncated glycans lacking galactose. Fibroblasts supplemented with galactose showed restoration of protein glycosylation and no evidence of glycogen accumulation. Dietary supplementation with galactose in six patients resulted in changes suggestive of clinical improvement. A new screening test showed good discrimination between patients and controls. CONCLUSIONS: Phosphoglucomutase 1 deficiency, previously identified as a glycogenosis, is also a congenital disorder of glycosylation. Supplementation with galactose leads to biochemical improvement in indexes of glycosylation in cells and patients, and supplementation with complex carbohydrates stabilizes blood glucose. A new screening test has been developed but has not yet been validated. Copyright © 2014 Massachusetts Medical Society.


Soufi M.,University of Marburg | Rust S.,Leibniz Institute For Arterioskleroseforschung | Walter M.,Institute of Laboratory Medicine | Schaefer J.R.,University of Marburg
Gene | Year: 2013

Familial hypercholesterolemia (FH) results from impaired catabolism of plasma low density lipoproteins (LDL), thus leading to high cholesterol, atherosclerosis, and a high risk of premature myocardial infarction. FH is commonly caused by defects of the LDL receptor or its main ligand apoB, together mediating cellular uptake and clearance of plasma LDL. In some cases FH is inherited by mutations in the genes of PCSK9 and LDLRAP1 (ARH) in a dominant or recessive trait. The encoded proteins are required for LDL receptor stability and internalization within the LDLR pathway. To detect the underlying genetic defect in a family of Turkish descent showing unregular inheritance of severe FH, we screened the four candidate genes by denaturing gradient gel electrophoresis (DGGE) mutation analysis. We identified different combinatory mixtures of LDLR- and LDLRAP1-gene defects as the cause for severe familial hypercholesterolemia in this family. We also show for the first time that a heterozygous LDLR mutation combined with a homozygous LDLRAP1 mutation produces a more severe hypercholesterolemia phenotype in the same family than a homozygous LDLR mutation alone. © 2013 Elsevier B.V.


Park J.H.,Universitatsklinikum Munster | Zuhlsdorf A.,Universitatsklinikum Munster | Wada Y.,Osaka University | Roll C.,Witten/Herdecke University | And 5 more authors.
Clinica Chimica Acta | Year: 2014

Background: The analysis of serum transferrin either by high-performance liquid chromatography (HPLC) or isoelectric focusing (IEF) is the standard diagnostic procedure in patients with the suspicion of a congenital disorder of glycosylation (CDG). Carbohydrate-deficient transferrin (CDT) is also analysed in monitoring programmes in cases of alcohol abuse. We report a novel transferrin variant that impairs the analysis using conventional methods and propose alternative forms of analysis. Methods: Transferrin samples were analysed using HPLC, immunoprecipitation followed by SDS-PAGE and IEF. Neuraminidase treatment followed by conventional IEF and electrospray ionization time of flight mass spectrometry (ESI-TOF MS) were applied before sequencing of the transferrin gene was performed. Results: The novel transferrin variant E592A, found both in homozygous and heterozygous form, causes an altered charge of the transferrin molecule, which changes the results of IEF and HPLC and mimics an increase in trisialo-transferrin. The change in charge can be detected either by neuraminidase digestion followed by IEF or by ESI-TOF MS. Conclusion: Conventional diagnostic methods for CDG are hindered by the novel transferrin E592A. Neuraminidase treatment followed by IEF and ESI-TOF MS can identify the mutation. The mutation appears to be functionally normal. © 2014 Elsevier B.V.


Wurde A.E.,Universitatsklinikum Munster Klinik | Reunert J.,Universitatsklinikum Munster Klinik | Rust S.,Leibniz Institute For Arterioskleroseforschung | Hertzberg C.,Vivantes Klinikum Neukolln | And 6 more authors.
Molecular Genetics and Metabolism | Year: 2012

Congenital disorders of glycosylation (CDG) are caused by enzymatic defects of the formation or processing of lipid-linked oligosaccharides and glycoproteins. Since the majority of proteins is glycosylated, a defect in a singular CDG enzyme leads to a multisytemic disease with secondary malfunction of thousands of proteins. CDG-Ij (DPAGT1-CDG) is caused by a defect of the human DPAGT1 (UDP-GlcNAc: Dolichol Phosphate N-Acetylglucosamine-1-Phosphotransferase), catalyzing the first step of N-linked glycosylation.So far the clinical phenotype of only one CDG-Ij patient has been described. The patient showed severe muscular hypotonia, intractable seizures, developmental delay, mental retardation, microcephaly and exotropia. Molecular studies of this patient revealed the heterozygous mutation c.660A. >. G (Y170C; paternal) in combination with an uncharacterized splicing defect (maternal). Two further mutations, c.890A. >. T (I297F) and c.162-8. G. >. A as a splicing defect were detected when analyzing DPAGT1 in two affected siblings of a second family.We report two new patients with the novel homozygous mutation, c.341. C. >. G (A114G), causing a severe clinical phenotype, characterized by hyperexcitability, intractable seizures, bilateral cataracts, progressive microcephaly and muscular hypotonia. Both our patients died within their first year of life.With the discovery of this novel mutation and a detailed clinical description we extend the clinical features of CDG-Ij in order to improve early detection of this disease. © 2012 Elsevier Inc..


Grundahl J.E.H.,Universitatsklinikum Munster Klinik | Guan Z.,Duke University | Rust S.,Leibniz Institute For Arterioskleroseforschung | Reunert J.,Universitatsklinikum Munster Klinik | And 10 more authors.
Molecular Genetics and Metabolism | Year: 2012

Congenital disorders of glycosylation (CDG) are caused by a dysfunction of glycosylation, an essential step in the manufacturing process of glycoproteins. This paper focuses on a 6-year-old patient with a new type of CDG-I caused by a defect of the steroid 5α reductase type 3 gene (SRD5A3). The clinical features were psychomotor retardation, pathological nystagmus, slight muscular hypotonia and microcephaly. SRD5A3 was recently identified encoding the polyprenol reductase, an enzyme catalyzing the final step of the biosynthesis of dolichol, which is required for the assembly of the glycans needed for N-glycosylation.Although an early homozygous stop-codon (c.57G. >. A [W19X]) with no functional protein was found in the patient, about 70% of transferrin (Tf) was correctly glycosylated. Quantification of dolichol and unreduced polyprenol in the patient's fibroblasts demonstrated a high polyprenol/dolichol ratio with normal amounts of dolichol, indicating that high polyprenol levels might compete with dolichol for the initiation of N-glycan assembly but without supporting normal glycosylation and that there must be an alternative pathway for dolichol biosynthesis. © 2011 Elsevier Inc..


Reunert J.,Universitatsklinikum Munster | Wentzell R.,Lukaskrankenhaus | Walter M.,Charité - Medical University of Berlin | Jakubiczka S.,University Hospital Magdeburg | And 4 more authors.
European Journal of Human Genetics | Year: 2012

Hutchinson-Gilford progeria syndrome (HGPS) is an important model disease for premature ageing. Affected children appear healthy at birth, but develop the first symptoms during their first year of life. They die at an average age of 13 years, mostly because of myocardial infarction or stroke. Classical progeria is caused by the heterozygous point mutation c.1824C > T in the LMNA gene, which activates a cryptic splice site. The affected protein cannot be processed correctly to mature lamin A, but is modified into a farnesylated protein truncated by 50 amino acids (progerin). Three more variations in LMNA result in the same mutant protein, but different grades of disease severity. We describe a patient with the heterozygous LMNA mutation c.1821G > A, leading to neonatal progeria with death in the first year of life. Intracellular lamin A was downregulated in the patient's fibroblasts and the ratio of progerin to lamin A was increased when compared with HGPS. It is suggestive that the ratio of farnesylated protein to mature lamin A determines the disease severity in progeria. © 2012 Macmillan Publishers Limited All rights reserved.


Rohlfing A.-K.,Universitatsklinikum Munster | Rust S.,Leibniz Institute For Arterioskleroseforschung | Reunert J.,Universitatsklinikum Munster | Tirre M.,Leibniz Institute For Arterioskleroseforschung | And 6 more authors.
Gene | Year: 2014

Congenital disorders of glycosylation (CDG) are a growing group of inherited metabolic disorders where enzymatic defects in the formation or processing of glycolipids and/or glycoproteins lead to variety of different diseases.The deficiency of GDP-Man:GlcNAc2-PP-dolichol mannosyltransferase, encoded by the human ortholog of ALG1 from yeast, is known as ALG1-CDG (CDG-Ik). The phenotypical, molecular and biochemical analysis of a severely affected ALG1-CDG patient is the focus of this paper. The patient's main symptoms were feeding problems and diarrhea, profound hypoproteinemia with massive ascites, muscular hypertonia, seizures refractory to treatment, recurrent episodes of apnoea, cardiac and hepatic involvement and coagulation anomalies.Compound heterozygosity for the mutations c.1145. T. >. C (M382T) and c.1312C. >. T (R438W) was detected in the patient's ALG1-coding sequence. In contrast to a previously reported speculation on R438W we confirmed both mutations as disease-causing in ALG1-CDG. © 2013 Elsevier B.V.


Dietzel M.,University of Munster | Dietzel M.,St Franziskus Hospital Munster | Farwick A.,University of Munster | Farwick A.,Leibniz Institute For Arterioskleroseforschung | Hense H.-W.,University of Munster
Ophthalmologe | Year: 2010

Age-related macular degeneration (AMD) is a complex disease of the central retina and the most important cause of blindness in the elderly. Exudative AMD in particular is responsible for cases of rapidly progressive visual impairment. Knowledge of pathogenetic mechanisms in exudative AMD is of particular importance for individual prognosis and the development of preventive and therapeutic options. Apart from age, smoking is the only consistently found major modifiable risk factor. Exudative AMD has a clear genetic basis with variants in the CFH and ARMS2 genes as major contributors. While ARMS2 seems to primarily influence the progression to exudative AMD, CFH seems equally related to the development of the exudative and atrophic forms of late AMD. Further differences relating to genetic and environmental risk factors in subgroups of exudative AMD are to be expected from future studies. © 2010 Springer-Verlag.


Scholz C.,Goethe University Frankfurt | Parcej D.,Goethe University Frankfurt | Ejsing C.S.,University of Southern Denmark | Robenek H.,Leibniz Institute For Arterioskleroseforschung | And 2 more authors.
Journal of Biological Chemistry | Year: 2011

The transporter associated with antigen processing (TAP)plays a key role in adaptive immunity by translocating proteasomal degradation products from the cytosol into the endoplasmic reticulum lumen for subsequent loading onto major histocompatibility (MHC) class I molecules. For functional and structural analysis of this ATP-binding cassette complex, we established the overexpression of TAP in the methylotrophic yeast Pichia pastoris. Screening of optimal solubilization and purification conditions allowed the isolation of the heterodimeric transport complex, yielding 30mgof TAP/liter of culture. Detailed analysis of TAP function in the membrane, solubilized, purified, and reconstituted states revealed a direct influence of the native lipid environment on activity. TAP-associated phospholipids, essential for function, were profiled by liquid chromatography Fourier transform mass spectrometry. The antigen translocation activity is stimulated by phosphatidylinositol and -ethanolamine, whereas cholesterol has a negative effect on TAP activity. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.


PubMed | University of Bonn, Emory University, Leibniz Institute For Arterioskleroseforschung, University of Munster and 2 more.
Type: Journal Article | Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience | Year: 2014

To assess the consequences of locus ceruleus (LC) degeneration and subsequent noradrenaline (NA) deficiency in early Alzheimers disease (AD), mice overexpressing mutant amyloid precursor protein and presenilin-1 (APP/PS1) were crossed with Ear2(-/-) mice that have a severe loss of LC neurons projecting to the hippocampus and neocortex. Testing spatial memory and hippocampal long-term potentiation revealed an impairment in APP/PS1 Ear2(-/-) mice, whereas APP/PS1 or Ear2(-/-) mice showed only minor changes. These deficits were associated with distinct synaptic changes including reduced expression of the NMDA 2A subunit and increased levels of NMDA receptor 2B in APP/PS1 Ear2(-/-) mice. Acute pharmacological replacement of NA by L-threo-DOPS partially restored phosphorylation of -CaMKII and spatial memory performance in APP/PS1 Ear2(-/-) mice. These changes were not accompanied by altered APP processing or amyloid peptide (A) deposition. Thus, early LC degeneration and subsequent NA reduction may contribute to cognitive deficits via CaMKII and NMDA receptor dysfunction independent of A and suggests that NA supplementation could be beneficial in treating AD.

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