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Bad Münster am Stein-Ebernburg, Germany

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.. Source

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.. Source

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