The International Registry of Werner Syndrome & Related Disorders (www.wernersyndrome.org) serves as a resource to ascertain and genotype nuclear pedigrees segregating mutations responsible for Werner syndrome (WS) and a range of other segmental progeroid syndromes. We shall establish and cryopreserve biological materials from these pedigrees and provide them to investigators around the world. We now propose to conduct systematic genome-wide searches for the gene mutations responsible for 41 progeroid cases with unknown causes and to seek evidence for therapeutic agents. We will employ a combination of SNP arrays and next generation sequencing; these have successfully identified novel mutations in a small number of cases. Those findings continue to support the concept of genomic instability as a major mechanism of biological aging. These loci highlight major roles in DNA repair and replication: WRN (DNA helicase/exonuclease), POLD1 (DNA polymerase delta), and SPRTN (recruitment of translesional DNA polymerase); nuclear structure and chromatin interaction (LMNA); an inhibitor of p53 (MDM2); regulation of dNTP pools (SAMHD1); and telomere maintenance (CTC1). We will also investigate why WS phenotypes are manifested only after puberty. We hypothesize that there may be an activation of compensatory mechanisms such as other RecQ helicases or DNA repair pathways during early development. To test our hypothesis, we will generate human pluripotent stem cell lines with and without WRN disease mutations using human pluripotent stem cells (hPSCs) and CRISPR and conduct transcriptome studies. Analysis will focus on these questions: how other RecQ helicases and DNA repair related genes are expressed in WS hPSCs compared to control hPSCs, how these expressions change following differentiation; whether or not these expressions correlated with the expression of cellular senescence genes. Cell lines generated by this project and all available patient materials will be made available to other investigators.
The International Registry of Werner Syndrome & Related Disorders recruits adult progeroid patients from all over the world and serves as a resource for colleagues who do basic research on the biology of aging. We propose to identify novel genes responsible for atypical forms of Werner syndrome and related disorders through whole genome sequencing. We will also investigate why WS symptoms start only after they reach to puberty using Werner syndrome stem cells.
| Oshima, Junko; Kato, Hisaya; Maezawa, Yoshiro et al. (2018) RECQ helicase disease and related progeroid syndromes: RECQ2018 meeting. Mech Ageing Dev 173:80-83 |
| Maezawa, Yoshiro; Kato, Hisaya; Takemoto, Minoru et al. (2018) Biallelic WRN Mutations in Newly Identified Japanese Werner Syndrome Patients. Mol Syndromol 9:214-218 |
| Horvath, Steve; Oshima, Junko; Martin, George M et al. (2018) Epigenetic clock for skin and blood cells applied to Hutchinson Gilford Progeria Syndrome and ex vivo studies. Aging (Albany NY) 10:1758-1775 |
| Mori, Takayasu; Yousefzadeh, Matthew J; Faridounnia, Maryam et al. (2018) ERCC4 variants identified in a cohort of patients with segmental progeroid syndromes. Hum Mutat 39:255-265 |
| Sargolzaeiaval, Forough; Zhang, Jiaming; Schleit, Jennifer et al. (2018) CTC1 mutations in a Brazilian family with progeroid features and recurrent bone fractures. Mol Genet Genomic Med 6:1148-1156 |
| Matsumoto, Namiko; Ohta, Yasuyuki; Deguchi, Kentaro et al. (2018) Characteristic Clinical Features of Werner Syndrome with a Novel Compound Heterozygous WRN Mutation c.1720+1G>A Plus c.3139-1G>C. Intern Med : |
| Hisama, Fuki Marie; Oshima, Junko (2018) Precision Medicine and Progress in the Treatment of Hutchinson-Gilford Progeria Syndrome. JAMA 319:1663-1664 |
| Maierhofer, Anna; Flunkert, Julia; Oshima, Junko et al. (2017) Accelerated epigenetic aging in Werner syndrome. Aging (Albany NY) 9:1143-1152 |
| Amalnath, S Deepak; Sargolzaeiaval, Forough; Oshima, Junko et al. (2017) Uncommon cause of cirrhosis-A case of Werner syndrome with a novel WRN mutation. Indian J Gastroenterol 36:323-325 |
| Oshima, Junko; Sidorova, Julia M; Monnat Jr, Raymond J (2017) Werner syndrome: Clinical features, pathogenesis and potential therapeutic interventions. Ageing Res Rev 33:105-114 |
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