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Cabanillas R.,Institute Medicina Oncologica Y Molecular Of Asturias | Cadinanos J.,Institute Medicina Oncologica Y Molecular Of Asturias | Villameytide J.A.,Centro Medico Of Asturias | Perez M.,Centro Medico Of Asturias | And 7 more authors.
American Journal of Medical Genetics, Part A | Year: 2011

Progeria syndromes are rare disorders that involve premature aging. Mutations in BANF1 have been recently reported to cause a new hereditary progeroid syndrome that we now propose to call the Néstor-Guillermo progeria syndrome (NGPS). We describe herein the clinical features of the first two NGPS patients, who phenocopy features of classic progerias (i.e., Hutchinson-Gilford progeria syndrome or mandibuloacral dysplasia), such as aged appearance, growth retardation, decreased subcutaneous fat, thin limbs, and stiff joints. However, these NGPS patients have a distinctive phenotype. In their early adulthood (32 and 24 years of age), they have no signs of cardiovascular impairment, diabetes mellitus, or hypertriglyceridemia. In contrast, they suffer profound skeletal abnormalities that affect their quality of life. The observed differences are of utmost importance to patients and their families and palliation of osseous manifestations is a priority, given their relatively long lifespan. We define NGPS as a chronic progeria because of its slow clinical course and relatively long survival, despite its early onset. Understanding the differences between progeria syndromes might contribute to the development of treatment strategies for common skeletal conditions, as well as aging itself. © 2011 Wiley Periodicals, Inc. Source

Introduction: Evidence-based medicine is transforming clinical practice because of its progressive implantation. Objectives: We considered studying whether LHRH analogues are agents of the same pharmacological class, i.e., whether they have the same clinical effect, using the approach to evidence-based medicine. Material and methods: PubMed was used as the main source of search. We have reviewed the evidence on the alleged «drug class effect» between analogues and the existing bibliographic support for their use in various medical indications. An evidence level and degree of recommendation have been assigned to each conclusion based on the «Scottish Intercollegiate Guidelines Network». Results: There are no studies designed to answer the question of a class effect between LHRH analogues or agonists. Reviews and meta-analyses have been performed on many other issues related to therapeutic management either with analogues, alone or in combination with surgery or radiation therapy. Direct comparisons do not allow for obtain definitive conclusions. Indirect evidence is obtained from randomized studies comparing the different LHRH analogues to other treatments used to obtain androgen deprivation. Other issues related to pharmacokinetics and pharmacodynamics supporting either the existence or non-existence of class effect were evaluated. Conclusions: The current available evidence is not enough to support a presumed «drug class effect» among the various analogues in the treatment of prostate carcinoma. © 2010 AEU. Source

Osorio F.G.,University of Oviedo | Navarro C.L.,French Institute of Health and Medical Research | Cadinanos J.,University of Oviedo | Cadinanos J.,Institute Medicina Oncologica Y Molecular Of Asturias | And 15 more authors.
Science Translational Medicine | Year: 2011

Hutchinson-Gilford progeria syndrome (HGPS) is caused by a point mutation in the LMNA gene that activates a cryptic donor splice site and yields a truncated form of prelamin A called progerin. Small amounts of progerin are also produced during normal aging. Studies with mouse models of HGPS have allowed the recent development of the first therapeutic approaches for this disease. However, none of these earlier works have addressed the aberrant and pathogenic LMNA splicing observed in HGPS patients because of the lack of an appropriate mouse model. Here, we report a genetically modified mouse strain that carries the HGPS mutation. These mice accumulate progerin, present histological and transcriptional alterations characteristic of progeroid models, and phenocopy the main clinical manifestations of human HGPS, including shortened life span and bone and cardiovascular aberrations. Using this animal model, we have developed an antisense morpholino-based therapy that prevents the pathogenic Lmna splicing, markedly reducing the accumulation of progerin and its associated nuclear defects. Treatment of mutant mice with these morpholinos led to a marked amelioration of their progeroid phenotype and substantially extended their life span, supporting the effectiveness of antisense oligonucleotide-based therapies for treating human diseases of accelerated aging. Source

Puente X.S.,University of Oviedo | Quesada V.,University of Oviedo | Osorio F.G.,University of Oviedo | Cabanillas R.,Institute Medicina Oncologica Y Molecular Of Asturias | And 9 more authors.
American Journal of Human Genetics | Year: 2011

Accelerated aging syndromes represent a valuable source of information about the molecular mechanisms involved in normal aging. Here, we describe a progeroid syndrome that partially phenocopies Hutchinson-Gilford progeria syndrome (HGPS) but also exhibits distinctive features, including the absence of cardiovascular deficiencies characteristic of HGPS, the lack of mutations in LMNA and ZMPSTE24, and a relatively long lifespan of affected individuals. Exome sequencing and molecular analysis in two unrelated families allowed us to identify a homozygous mutation in BANF1 (c.34G>A [p.Ala12Thr]), encoding barrier-to-autointegration factor 1 (BAF), as the molecular abnormality responsible for this Mendelian disorder. Functional analysis showed that fibroblasts from both patients have a dramatic reduction in BAF protein levels, indicating that the p.Ala12Thr mutation impairs protein stability. Furthermore, progeroid fibroblasts display profound abnormalities in the nuclear lamina, including blebs and abnormal distribution of emerin, an interaction partner of BAF. These nuclear abnormalities are rescued by ectopic expression of wild-type BANF1, providing evidence for the causal role of this mutation. These data demonstrate the utility of exome sequencing for identifying the cause of rare Mendelian disorders and underscore the importance of nuclear envelope alterations in human aging. © 2011 The American Society of Human Genetics. Source

Ugalde A.P.,University of Oviedo | Ramsay A.J.,University of Oviedo | De La Rosa J.,Institute Medicina Oncologica Y Molecular Of Asturias | Varela I.,University of Oviedo | And 5 more authors.
EMBO Journal | Year: 2011

Aging is a multifactorial process that affects most of the biological functions of the organism and increases susceptibility to disease and death. Recent studies with animal models of accelerated aging have unveiled some mechanisms that also operate in physiological aging. However, little is known about the role of microRNAs (miRNAs) in this process. To address this question, we have analysed miRNA levels in Zmpste24-deficient mice, a model of Hutchinson-Gilford progeria syndrome. We have found that expression of the miR-29 family of miRNAs is markedly upregulated in Zmpste24 -/- progeroid mice as well as during normal aging in mouse. Functional analysis revealed that this transcriptional activation of miR-29 is triggered in response to DNA damage and occurs in a p53-dependent manner since p53 -/- murine fibroblasts do not increase miR-29 expression upon doxorubicin treatment. We have also found that miR-29 represses Ppm1d phosphatase, which in turn enhances p53 activity. Based on these results, we propose the existence of a novel regulatory circuitry involving miR-29, Ppm1d and p53, which is activated in aging and in response to DNA damage. © 2011 European Molecular Biology Organization. Source

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