Life with too much polyprenol: polyprenol reductase deficiency

• Published in: Molecular genetics and metabolism 2012-04, Vol.105 (4), p.642-651
• Main Authors: Gründahl, J.E.H., Guan, Z., Rust, S., Reunert, J., Müller, B., Du Chesne, I., Zerres, K., Rudnik-Schöneborn, S., Ortiz-Brüchle, N., Häusler, M.G., Siedlecka, J., Swiezewska, E., Raetz, C.R.H., Marquardt, T.
• Format: Article
• Language: English
• Subjects: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase - genetics; Cells, Cultured; Chromatography, High Pressure Liquid; Congenital disorders of glycosylation; Congenital Disorders of Glycosylation - diagnosis; Congenital Disorders of Glycosylation - enzymology; Congenital Disorders of Glycosylation - genetics; Consanguinity; Dolichol; Dolichol - metabolism; Electrophoresis, Polyacrylamide Gel; Enzymes; Female; Fibroblasts; Genetic Complementation Test; Glycoproteins; Glycosylation; Homozygote; Humans; Immunoprecipitation; Infant, Newborn; Isoelectric Focusing; Male; Membrane Proteins - genetics; Mental retardation; Microencephaly; Motor skill learning; Mutation - genetics; N-glycans; Nystagmus; Pedigree; Pentanols - metabolism; Polyprenol reductase; Polysaccharides; Psychomotor retardation; reductase; SRD5A3-CDG; Steroid hormones; Transferrin
• ISSN: 1096-7192; 1096-7206
• DOI: 10.1016/j.ymgme.2011.12.017

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. ► A new patient with polyprenol-reductase deficiency. ► An early homozygous stop-codon with no functional protein was found. ► About 70% of transferrin is correctly glycosylated. ► A high polyprenol/dolichol ratio with normal amounts of dolichol. ► Therapeutic approaches.