title: A defect in dolichol phosphate biosynthesis causes a new inherited disorder with death in early infancy.
abstract: The following study describes the discovery of a new inherited metabolic disorder, dolichol kinase (DK1) deficiency. DK1 is responsible for the final step of the de novo biosynthesis of dolichol phosphate. Dolichol phosphate is involved in several glycosylation reactions, such as N-glycosylation, glycosylphosphatidylinositol (GPI)-anchor biosynthesis, and C- and O-mannosylation. We identified four patients who were homozygous for one of two mutations (c.295T-->A [99Cys-->Ser] or c.1322A-->C [441Tyr-->Ser]) in the corresponding hDK1 gene. The residual activity of mutant DK1 was 2%-4% when compared with control cells. The mutated alleles failed to complement the temperature-sensitive phenotype of DK1-deficient yeast cells, whereas the wild-type allele restored the normal growth phenotype. Affected patients present with a very severe clinical phenotype, with death in early infancy. Two of the patients died from dilative cardiomyopathy.
authors.affiliation: Klinik fur Kinder und Jugendmedizin, Munster, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kranz
authors.forename: Christoph
authors.initials: C
authors.lastname: Jungeblut
authors.forename: Jonas
authors.initials: J
authors.lastname: Denecke
authors.forename: Anne
authors.initials: A
authors.lastname: Erlekotte
authors.forename: Christina
authors.initials: C
authors.lastname: Sohlbach
authors.forename: Volker
authors.initials: V
authors.lastname: Debus
authors.forename: Hans Gerd
authors.initials: HG
authors.lastname: Kehl
authors.forename: Erik
authors.initials: E
authors.lastname: Harms
authors.forename: Anna
authors.initials: A
authors.lastname: Reith
authors.forename: Sonja
authors.initials: S
authors.lastname: Reichel
authors.forename: Helfried
authors.initials: H
authors.lastname: Grobe
authors.forename: Gerhard
authors.initials: G
authors.lastname: Hammersen
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schwarzer
authors.forename: Thorsten
authors.initials: T
authors.lastname: Marquardt
mesh_terms: D002311:Cardiomyopathy, Dilated / Q000401:mortality*; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D004288:Dolichol Phosphates / Q000096:biosynthesis*; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D005816:Genetic Complementation Test; D030342:Genetic Diseases, Inborn / Q000235:genetics / Q000378:metabolism / Q000401:mortality*; D006031:Glycosylation; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency* / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D012867:Skin / Q000166:cytology
chemical_list: D004288:Dolichol Phosphates; D017853:Phosphotransferases (Alcohol Group Acceptor); C020087:dolichol kinase