Human progeroid syndromes, aging and cancer: new genetic and epigenetic insights into old questions
ABSTRACT Disorders in which individuals exhibit certain features of aging early in life are referred to as segmental progeroid syndromes. With the progress that has been made in understanding the etiologies of these conditions in the past decade, potential therapeutic options have begun to move from the realm of improbability to initial stages of testing. Among these syndromes, relevant advances have recently been made in Werner syndrome, one of several progeroid syndromes characterized by defective DNA helicases, and Hutchinson-Gilford progeria syndrome, which is characterized by aberrant processing of the nuclear envelope protein lamin A. Although best known for their causative roles in these illnesses, Werner protein and lamin A have also recently emerged as key players vulnerable to epigenetic changes that contribute to tumorigenesis and aging. These advances further demonstrate that understanding progeroid syndromes and introducing adequate treatments will not only prove beneficial to patients suffering from these dramatic diseases, but will also provide new mechanistic insights into cancer and normal aging processes.
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ABSTRACT: Background Premature aging syndromes recapitulate many aspects of natural aging and provide an insight into this phenomenon at a molecular and cellular level. The progeria syndromes appear to cause rapid aging through disruption of normal nuclear structure. Recently, a coding mutation (c.34G¿>¿A [p.A12T]) in the Barrier to Autointegration Factor 1 (BANF1) gene was identified as the genetic basis of Néstor-Guillermo Progeria syndrome (NGPS). This mutation was described to cause instability in the BANF1 protein, causing a disruption of the nuclear envelope structure.ResultsHere we demonstrate that the BANF1 A12T protein is indeed correctly folded, stable and that the observed phenotype, is likely due to the disruption of the DNA binding surface of the A12T mutant. We demonstrate, using biochemical assays, that the BANF1 A12T protein is impaired in its ability to bind DNA while its interaction with nuclear envelope proteins is unperturbed. Consistent with this, we demonstrate that ectopic expression of the mutant protein induces the NGPS cellular phenotype, while the protein localizes normally to the nuclear envelope.Conclusions Our study clarifies the role of the A12T mutation in NGPS patients, which will be of importance for understanding the development of the disease.BMC Molecular Biology 12/2014; 15(1):27. DOI:10.1186/s12867-014-0027-z · 2.06 Impact Factor
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ABSTRACT: Background SHORT syndrome is a rare autosomal dominant condition whose name is the acronym of short stature, hyperextensibility of joints, ocular depression, Rieger anomaly and teething delay (MIM 269880). Additionally, the patients usually present a low birth weight and height, lipodystrophy, delayed bone age, hernias, low body mass index and a progeroid appearance. Case presentation In this study, we used whole-exome sequencing approaches in two patients with clinical features of SHORT syndrome. We report the finding of a novel mutation in PIK3R1 (c.1929_1933delTGGCA; p.Asp643Aspfs*8), as well as a recurrent mutation c.1945C > T (p.Arg649Trp) in this gene. Conclusions We found a novel frameshift mutation in PIK3R1 (c.1929_1933delTGGCA; p.Asp643Aspfs*8) which consists of a deletion right before the site of substrate recognition. As a consequence, the protein lacks the position that interacts with the phosphotyrosine residue of the substrate, resulting in the development of SHORT syndrome.BMC Medical Genetics 05/2014; 15(1):51. DOI:10.1186/1471-2350-15-51 · 2.45 Impact Factor
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ABSTRACT: Ataxia telangiectasia (AT) is a severe hereditary autosomal recessive neurodegenerative disease associated with accelerated aging and caused by mutation in both alleles of the atm gene. This gene encodes a key protein of cell response to DNA damage—the ATM protein kinase. Normally, upon formation of DNA double strand breaks, ATM is autophosphorylated and its active form phospho-ATM (P-ATM) appears. Here, we describe a mosaic form of AT in which cells of the same patient with a normal atm gene exhibited the accumulation of P-ATM in response to DNA double-strand breaks-inducing factors whereas, in cells bearing a mutant form of atm, P-ATM was not detected. Epigenetic markers, such as the histone deacetylases SIRT1 and SIRT6, and trimethylated forms of histone H3, H3K9me3 and H3K27me3, were studied in the nuclei of primary fibroblasts derived from patients with different forms of AT, and an increase in the SIRT6 level was revealed.Cell and Tissue Biology 01/2015; 9(1):53-63. DOI:10.1134/S1990519X15010058