Werner Syndrome and the WRN Gene

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Werner Syndrome and the WRN Gene

Werner Syndrome (WS) is essentially early onset aging and was first described formally in Otto Werner's doctoral dissertation (Advances in Experimental Medicine and Biology, 1985). There are similar maladies that produce aging effects, perhaps one of the more famous being Hutchinson-Gilford syndrome (progeria) that affects children beginning around age two (Progeria, 2002). WS is a autosomal, recessive, inherited disease, meaning typically parents are carriers and it takes a mutated  WRN gene from both parents for a child to be affected (Raghavendra et al., 2014). Typically symptoms begin to show when children reach puberty. At that time growth slows significantly or stops and reproductive systems fail to fully develop. Graying hair often arrives in the mid-twenties and progressive aging symptoms begin to occur in the thirties and forties. Additional symptoms may include but are not limited to arteriosclerosis, cataracts, skin atrophy, graying and loss of hair, wrinkles, loss of fat, atherosclerosis, diabetes, osteoporosis, and a high incidence cancers. (Online Mendelian Inheritance in Man [OMIM], 2022; Ozgenc & Loeb, 2005; Raghavendra et al., 2014). Aging effects of this disease include loss of telomere length, loss of protein regulation, mitochondrial malfunction, genomic instability, decreased nutrient sensing, stem cell depletion, and epigenetic alterations (Raghavendra et al., 2014).  Lifespan is generally short with a mean average age of death being 47 years (Ozgenc & Loeb, 2005), median 54 years (Huang, 2006; Muftuoglu, 2008).

The WRN gene was first positively identified in 1994 (Oshima et al., 1994) The gene sits on chromosome 8, band 8p12, base pairs 31,033,810 - 31,176,138, has six transcripts, and 37 exons  (National Center for Biotechnology Information [NCBI], 2022; Oshima et al., 1994; Yu et al., 1996). It posses "a N-terminal 3' to 5' exonuclease domain, an ATP-dependent helicase domain and RQC (RecQ helicase conserved region) domain in its central region, and a C-terminal HRDC (helicase RNase D C-terminal) domain and nuclear localization signal" (NCBI, 2022, Summary). The WRN gene is involved multiple pathways and processes including DNA duplex unwinding/recombining/replication/synthesis, aging, brain development, cellular senescence, response to oxidative stress, double-strand break repair, homologous recombination, single strand annealing, D-loop resolution, cell cycle, telomere maintenance/extension/regulation, protein metabolism, and the p53 pathway (NCBI, 2022). The protein   translated from the WRN gene is named the WRN protein ( Raghavendra et al., 2014; The Universal Protein Resource [UniProt], 2022). 

Over time there have been at least 80 mutations identified that affect the WRN gene (Coppedè, 2021; Muftuoglu, 2008; Yu et al., 1996). Most of these cause the gene to produce a shortened, malformed, or unstable protein that is destroyed immediately or soon after translation (Huang, 2006). Some of the defects cause a loss of nuclear localization at the C-terminus which will cause failure of the protein to be identified for transport into the nucleus where it performs the vast majority of its work (Coppedè, 2021). Insertion of stop codons occur in multiple locations causing premature cessation of protein coding. "The c.1105C>T mutation creating a stop codon in exon 9 (p.Arg369*) is the most common mutation in non-Japanese populations and the second most common one in Japan" (Coppedè, 2021, p. 288). Frame-shift and splice site mutations also occur which cause exons to be skipped. The loss of protein function due to any of the above mutations causes the Werner Syndrome (Coppedè, 2021).

References

Coppedè F. (2021). Mutations Involved in Premature-Ageing Syndromes. The Application of Clinical Genetics, 14, 279–295. doi.org/10.2147/TACG.S273525

Huang, S., Lee, L., Hanson, N. B., Lenaerts, C., Hoehn, H., Poot, M., Rubin, C. D., Chen, D. F., Yang, C. C., Juch, H., Dorn, T., Spiegel, R., Oral, E. A., Abid, M., Battisti, C., Lucci-Cordisco, E., Neri, G., Steed, E. H., Kidd, A., Isley, W., … Oshima, J. (2006). The Spectrum of WRN Mutations in Werner Syndrome Patients. Human Mutation, 27(6), 558–567. doi.org/10.1002/humu.20337

National Center for Biotechnology Information. (August 14, 2022).WRN RecQ Like Helicase [ Homo sapiens (human) ]. National Library of Medicine. Retrieved on September 1, 2022 from https://www.ncbi.nlm.nih.gov/gene/7486

Muftuoglu, M., Oshima, J., von Kobbe, C., Cheng, W. H., Leistritz, D. F., & Bohr, V. A. (2008). The Clinical Characteristics of Werner Syndrome: Molecular and Biochemical Diagnosis. Human Genetics, 124(4), 369–377. doi.org/10.1007/s00439-008-0562-0

On Cataract in Conjunction with Scleroderma. Otto Werner, doctoral dissertation, 1904, Royal Ophthalmology Clinic, Royal Christian Albrecht University of Kiel. (1985). Advances in Experimental Medicine and Biology, 190, 1–14. DOI: 10.1007/978-1-4684-7853-2_1. (In translators notes (Hoehn, H.) preview retrieved on Sept 3, 2022 from https://link.springer.com/chapter/10.1007/978-1-4684-7853-2_1).

OMIM. (March 1, 2022). WERNER SYNDROME; WRN.  John Hopkins University. Retrieved on September 1, 2022 from https://www.omim.org/entry/277700

Oshima, J., Yu, C. E., Boehnke, M., Weber, J. L., Edelhoff, S., Wagner, M. J., Wells, D. E., Wood, S., Disteche, C. M., & Martin, G. M. (1994). Integrated Mapping Analysis of the Werner Syndrome Region of Chromosome 8. Genomics, 23(1), 100–113. doi.org/10.1006/geno.1994.1464

Ozgenc, A., & Loeb, L. A. (2005). Current Advances in Unraveling the Function of the Werner Syndrome Protein. Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis, 577(1), 237–251. doi.org/10.1016/j.mrfmmm.2005.03.020

Progeria. (2002). Mayo Clinic. Retrieved on September 3, 2022 from https://www.mayoclinic.org/diseases-conditions/progeria/symptoms-causes/syc-20356038 

Raghavendra A. Shamanna, Deborah L. Croteau, Jong-Hyuk Lee, & Vilhelm A. Bohr. (2017). Recent Advances in Understanding Werner Syndrome [version 1; referees: 3 approved]. F1000Research, 6. doi.org/10.12688/f1000research.12110.1

UniProt. (August 3, 2022). Q14191 · WRN_HUMAN. European Bioinformatics Institute. Retrieved on September 1, 2022 from https://www.uniprot.org/uniprotkb/Q14191/entry

Yu, C.-E., Oshima, J., Fu, Y.-H., Wijsman, E. M., Hisama, F., Alisch, R., Matthews, S., Nakura, J., Miki, T., Ouais, S., Martin, G. M., Mulligan, J., & Schellenberg, G. D. (1996). Positional Cloning of the Werner’s Syndrome Gene. Science, 272(5259), 258–262. DOI: 10.1126/science.272.5259.258

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