Life with too much polyprenol: polyprenol reductase deficiency

Abstract

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.

Phenotypic Expansion of Congenital Disorder of Glycosylation Due to SRD5A3 Null Mutation

“…It affects protein N-glycosylation, as well as the synthesis of mannose-linked glycans, C-mannosylation, and glycophospholipid anchor synthesis. SRD5A3-CDG is characterized by neurological and ophthalmological findings such as nystagmus, visual impairment, microphthalmia, cataract, coloboma (iris, chorioretinal), optic disk hypoplasia, and optic nerve hypoplasia/atrophy (Assmann et al 2001;Prietsch et al 2002;Al-Gazali et al 2008;Kahrizi et al 2009Kahrizi et al , 2011Morava et al 2009Morava et al , 2010Cantagrel et al 2010;Gr€ undahl et al 2012;Kara et al 2014;Kasapkara et al 2012).…”

POLYPRENOL REDUCTASE2 Deficiency Is Lethal in Arabidopsis Due to Male Sterility

“…Moreover, the excess of polyprenols accumulated in SRD5A3 patients' cells is considered toxic due to the polyprenol versus Dol competition during polyisoprenoidPPtetradecasaccharide assembly (Gründahl et al, 2012). In Arabidopsis leaves, the content of polyprenols (Pren-10 dominating) highly exceeds that of Dols (Dol-16 dominating) (Gawarecka and Swiezewska, 2014), but the considerable difference of their chain length suggests that the substrate specificity of Dol kinase and/or saccharyl transferases protects these cells against the potential toxicity of Pren excess.…”

“…Finally, an alternative albeit still not recognized pathway leading to Dol has been postulated in yeast and human to account for the residual Dol and partially retained protein glycosylation found in DFG10 and SDR5A3 and null mutants (Cantagrel et al, 2010;Gründahl et al, 2012). Whether a similar, SRD5A3/PPRDindependent Dol-producing pathway functions in plants awaits clarification (Supplemental Figure 10).…”

News on Clinical Details and Treatment in PGM1-CDG

“…Lower panel: quantification by HPLC. Horizontal blue and red shading indicate the reference ranges for tetrasialotransferrin and hyposialotransferrin, respectively (Grundahl et al 2012). Doubleband of patients disialotransferrin, known as "C2" variant (Helander et al 2001), is explained in the Supplement.…”

“…2). Tetrasialotransferrin increased to 87 % under galactose (normal range: 85.6-94% [mean AE 2 SD, Grundahl et al 2012]). After stopping galactose supplementation, glycosylation efficiency returned to pretreatment values.…”