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Bad Münster am Stein-Ebernburg, Germany

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.

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.

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.,Charite - 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.

Dietzel M.,University of 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.

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