SRD5A3 Is Required for Converting Polyprenol to Dolichol and Is Mutated in a Congenital Glycosylation Disorder

Neurogenetics Laboratory, Institute for Genomic Medicine, Howard Hughes Medical Institute, Department of Neurosciences and Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
Cell (Impact Factor: 32.24). 07/2010; 142(2):203-17. DOI: 10.1016/j.cell.2010.06.001
Source: PubMed

ABSTRACT N-linked glycosylation is the most frequent modification of secreted and membrane-bound proteins in eukaryotic cells, disruption of which is the basis of the congenital disorders of glycosylation (CDGs). We describe a new type of CDG caused by mutations in the steroid 5alpha-reductase type 3 (SRD5A3) gene. Patients have mental retardation and ophthalmologic and cerebellar defects. We found that SRD5A3 is necessary for the reduction of the alpha-isoprene unit of polyprenols to form dolichols, required for synthesis of dolichol-linked monosaccharides, and the oligosaccharide precursor used for N-glycosylation. The presence of residual dolichol in cells depleted for this enzyme suggests the existence of an unexpected alternative pathway for dolichol de novo biosynthesis. Our results thus suggest that SRD5A3 is likely to be the long-sought polyprenol reductase and reveal the genetic basis of one of the earliest steps in protein N-linked glycosylation.

Download full-text


Available from: Vincent Cantagrel, Sep 26, 2015
36 Reads
  • Source
    • "The steroid products of the 5α-Rs pathways undergo further metabolism by the 3α-hydroxy-steroid dehydrogenase (3α-HSD) to produce a host of active neurosteroids with important physiological function, in many tissues including the central nervous system (CNS) (Fig. 1) [1,2]. In addition, synthesis of dolichol from polyprenol was recently shown to require the activity of the 5α-R type 3 [3]. Since dolichol phosphate is critical in N-glycosylation of membrane proteins, inhibition of the activity of 5α-R type 3 may have undesirable effects as a result of attenuation of this and other biochemical pathways important in modulating cellular function [4]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: With aging, abnormal benign growth of the prostate results in benign prostate hyperplasia (BPH) with concomitant lower urinary tract symptoms (LUTS). Because the prostate is an androgen target tissue, and transforms testosterone into 5α-dihydrotestosterone (5α-DHT), a potent androgen, via 5α-reductase (5α-R) activity, inhibiting this key metabolic reaction was identified as a target for drug development to treat symptoms of BPH. Two drugs, namely finasteride and dutasteride were developed as specific 5α-reductase inhibitors (5α-RIs) and were approved by the U.S. Food and Drug Administration for the treatment of BPH symptoms. These agents have proven useful in the reducing urinary retention and minimizing surgical intervention in patients with BPH symptoms and considerable literature exists describing the benefits of these agents. In this review we highlight the adverse side effects of 5α-RIs on sexual function, high grade prostate cancer incidence, central nervous system function and on depression. 5α-Rs isoforms (types 1-3) are widely distributed in many tissues including the central nervous system and inhibition of these enzymes results in blockade of synthesis of several key hormones and neuro-active steroids leading to a host of adverse effects, including loss of or reduced libido, erectile dysfunction, orgasmic dysfunction, increased high Gleason grade prostate cancer, observed heart failure and cardiovascular events in clinical trials, and depression. Considerable evidence exists from preclinical and clinical studies, which point to significant and serious adverse effects of 5α-RIs, finasteride and dutasteride, on sexual health, vascular health, psychological health and the overall quality of life. Physicians need to be aware of such potential adverse effects and communicate such information to their patients prior to commencing 5α-RIs therapy.
    Korean journal of urology 06/2014; 55(6):367-379. DOI:10.4111/kju.2014.55.6.367
  • Source
    • "The 46, XY disorders of sex development (DSD) are presently classified in three main categories [1]: disorders of gonad development such as gonadal dysgenesis, disorders of androgen biosynthesis and metabolism and disorders related to androgen sensitivity (the androgen insensitivity syndrome, AIS). Within the second category, genetic causes have been identified, such as loss of function mutations of the LH receptor gene (LHCGR), 17β hydroxysteroid dehydrogenase deficiency type 3, related to mutations of the HSD17B3 gene and loss of function mutations of the SRD5A2 gene, responsible for 5α-reductase type 2deficiencywhich is one of the three 5α-reductase isoforms expressed in humans [2]. In the third category, androgen receptor (AR) mutations have been identified in patients with mild, partial or complete androgen insensitivity syndromes (AIS) [1]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Testicular morphology and immunohistochemical studies have never been reported in genetically documented adult patients with 5 alpha-reductase type 2 deficiency (5α-R2 deficiency). Case presentation We describe the testicular histopathology of a 17-year-old XY subject with 5α-R2 deficiency caused by the recurrent homozygous Gly115Asp loss of function mutation of the SRD5A2 gene.We also performed an immunohistochemical analysis in order to further study the relationship between seminiferous tubules structure, Sertoli cell differentiation and androgenic signaling impairment in this case. We thus evaluated the testicular expression of the anti-Müllerian hormone (AMH), androgen receptor (AR) and 3β-hydroxysteroid dehydrogenase (3βHSD). Histological analysis revealed a heterogeneous aspect with a majority (92%) of seminiferous tubules (ST) presenting a mature aspect but containing only Sertoli cells and devoid of germ cells and spermatogenesis. Focal areas of immature ST (8%) were also found. Testicular AR and 3βHSD expression were detected in adult male control, 5α-R2 deficiency and CAIS subjects. However, AMH expression was heterogeneous (detectable only in few AR negative prepubertal ST, but otherwise repressed) in the 5α-R2 deficiency, conversely to normal adult testis in which AMH was uniformly repressed and to an adult CAIS testis in which AMH was uniformly and strongly expressed. Conclusion Intratesticular testosterone can repress AMH by itself, independently of its metabolism into dihydrotestosterone. We also compare our results to the few post pubertal cases of 5α-R2 deficiency with available histological testicular description, reported in the literature. We will discuss these histological findings, in the more general context of evaluating the fertility potential of these patients if they were raised as males and were azoospermic.
    BMC Endocrine Disorders 05/2014; 14(1):43. DOI:10.1186/1472-6823-14-43 · 1.71 Impact Factor
  • Source
    • "In 5-AR2 deficient men, Thiele et al.31 reported that 5-AR1 may play a critical role in the masculinization of 5-AR2 deficient men. Cantagrel et al.16 reported that patients with mutations in SRD5A3 exhibited a multisystemic syndrome with psychomotor delay, cerebellar vermis hypoplasia and eye malformation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The development of human benign or malignant prostatic diseases is closely associated with androgens, primarily testosterone (T) and dihydrotestosterone (DHT). T is converted to DHT by 5-alpha reductase (5-AR) isozymes. Differential expression of 5-AR isozymes is observed in both human benign and malignant prostatic tissues. 5-AR inhibitors (5-ARI) are commonly used for the treatment of benign prostatic hyperplasia (BPH) and were once promoted as chemopreventive agents for prostate cancer (PCa). This review discusses the role of the differential expression of 5-AR in the normal development of the human prostate and in the pathogenesis and progression of BPH and PCa.
    Asian Journal of Andrology 01/2014; 16(2). DOI:10.4103/1008-682X.123664 · 2.60 Impact Factor
Show more