Telomerase mutations have been reported with several human genetic diseases such as DKC, IPF etc., I would like to know whether any telomerase (either in TERT, TERC or DKC1) mutations have been reported/ linked to Werner Syndrome?
The WS gene (WRN) encodes a member of the RecQ family of DNA helicases and it has previously been reported that fibroblasts derived from the patients with Werner syndrome show the accelerated senescence much the same as in vivo phenotype typical of significant telomere shrinkage. Fiona S. Wyllie et al. have demonstrated that AG03141B:pBABE-hTERT clones, the immortalization of the fibroblasts of Werner syndrome, rescued the phenotype of accelerated aging. That is why TERT is considered to be an essential molecule to determine the cellular behavior of Werner syndrome.
I would like to add the informative recent paper. Cheryl M. Koh et al. have just published a paper from JCI in which they tell that TERT had a dramatic effect on steady-state levels of MYC by suppressing the ubiquitin modification of the proto-oncogene. As you know well, the patients with Werner syndrome tend to present tumors such as thrroid cancer and sarcoma. The abnormal regulation of c-Myc, even though c-Myc is easier to receive uniquitin-modification, might be related to the tumor development.
[Ref]
Telomerase regulates MYC-driven oncogenesis independent of its reverse transcriptase activity
Cheryl M. Koh ... Ernesto Guccione, Vinay Tergaonkar
Published April 20, 2015
Citation Information: J Clin Invest. 2015. doi:10.1172/JCI79134.
Heterozygous de novo mutations in the Lamin A/C gene (LMNA) have been described to cause Atypical Werner Syndrome, but to my knowledge none in TERT or TERC genes.
But there are still several genetically uncharacterized AWS patients ...
The mutation in the WRN gene that causes Werner syndrome is autosomal and recessive, meaning that sufferers must inherit a copy of the gene from each parent. Patients display rapid premature aging beginning in young adulthood, usually in their early twenties. It is thought that the WRN helicase activity is important not only for DNA repair and recombination, but also for maintaining telomere length and stability. Thus, WRN helicase is important for preventing catastrophic telomere loss during DNA replication. In a normal cell, the telomeres (the ends of chromosomes) undergo repeated shortening during the cell cycle, which can prevent the cell from dividing and multiplying. This event can be counteracted by telomerase, an enzyme that extends the ends of the chromosomes by copying the telomeres and synthesizing an identical, but new end that can be added to the existing chromosome. However, patients with Werner syndrome often exhibit accelerated telomere shortening, indicating that there may be a connection between the loss of the WRN helicase activity and telomere and cell instability. While evidence shows that telomere dysfunction is consistent with the premature aging in WS, it has yet to be determined if it is the actual cause of the genomic instability observed in cells and the high rate of cancer in WS patients
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