A Defect in Dolichol Phosphate Biosynthesis Causes a New Inherited Disorder with Death in Early Infancy

Klinik fur Kinder und Jugendmedizin, Munster, Germany.
The American Journal of Human Genetics (Impact Factor: 10.93). 03/2007; 80(3):433-40. DOI: 10.1086/512130
Source: PubMed


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.

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Available from: Hans Gerd Kehl, Jan 20, 2014
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    • "Phosphates of these PI-OH besides analogous membranotropic behavior serve as the specific membrane-bound intermediary carriers for glycosyl and oligosaccharyl residues in glycan biosynthetic pathways responsible for the production of cellular components such as N-linked glycoproteins or bacterial peptidoglycan (Hartley and Imperiali 2012; Jones et al. 2009; Larkin and Imperiali 2011; Schenk et al. 2001). These functions of PI are of extraordinary significance because genetic disturbances of biosynthetic pathways in which PI and their derivatives participate lead to grave (sometimes fatal) consequences known as congenital disorders (Cantagrel and Lefeber 2011; Cantagrel et al. 2010; Goreta et al. 2012; Grundahl et al. 2012; Kranz et al. 2007). Similar abnormalities are observed at fetal alcohol syndrome particularly as a result of suppression of biosynthesis of dolichol (dolichyl phosphate) from mevalonate by ethyl alcohol (Binghorst et al. 2012). "
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    • "al manifestations included microcephaly , ' ' parchment - like ' ' ichthyosis with loss of hair , eyebrows and eyelashes , intractable seizures , severe hypotonia with elevated CK , severe liver dysfunction , and progressive dilated cardiomyopathy resulting in death within 1 year . measured in skin fibroblasts was 5% or less of parallel controls [ Kranz et al . , 2007 ] . Subsequently , Lefeber reported 11 patients ( 5 – 13 years of age ) with pro - gressive dilated cardiomyopathy , mild hypotonia with elevated CK levels and persistent elevations of transaminases , and mild coagulopathy [ Lefeber et al . , 2011 ] . Half of the probands had variable ichthyosis , and mild intellectual disabili - ty was"
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