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Molecular Basis of Progeroid Diseases

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Clinical Genetics and Genomics of Aging

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Abstract

Aging is a universal and inevitable process that affects virtually all living organisms; in humans, aging is characterized by a gradual decline of physical and psychological functions that ultimately leads to death. Over the past decades, the study of progeroid syndromes, a group of premature aging disorders that recapitulates multiple features of physiological aging, has provided insightful information toward the identification of mechanisms underlying aging. In this chapter, we provide an updated description of the main progeroid syndromes affecting humans, including their clinical manifestations and the genetic and molecular basis underlying their pathogenesis. Most progeroid syndromes originate from defective DNA repair and nuclear structure systems, highlighting a key role of genome stability in aging. A special emphasis is given to Hutchinson Gilford Progeria Syndrome (HGPS), the most well-studied premature aging disorder, which is characterized by accelerated aging and early death due to cardiovascular complications. HGPS is typically caused by a silent mutation in the LMNA gene that provokes the expression of progerin, a dominant-negative mutant protein that anchors aberrantly to the nuclear envelope, thereby inducing cellular toxicity and organismal detriment. Thus, we provide a description of established cellular and animal models for HGPS and discuss the perspectives for therapeutic developments, including an updated presentation of treatment strategies that have been tested so far in vitro (human HGPS fibroblast cultures) and in vivo (HGPS mice models) and in clinical trials, with argumentation of their main limitations.

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Abbreviations

APS:

Atypical Progeria Syndromes

ASO:

Antisense Oligonucleotides

BAC:

Bacterial Artificial Chromosome

BS:

Bloom Syndrome

CRM1:

Chromosomal Region Maintenance 1

CS:

Cockayne Syndrome

CSA:

Cockayne Syndrome protein A

CSB:

Cockayne Syndrome protein B

DSB:

Double-Strand Break

FTI:

Farnesyltransferase Inhibitors

HGPS:

Hutchinson-Gilford Progeria Syndrome

iPSCs:

induced Pluripotent Stem Cells

MAD:

Mandibuloacral Dysplasia

mTOR:

mammalian Target of Rapamycin

NE:

Nuclear Envelope

NER:

Nucleotide Excision Repair

NES:

Nuclear Export Signal

NGPS:

Nestor-Guillermo Progeria Syndrome

NPC:

Nuclear Pore Complexes

Prx1:

Paired related homeobox 1

RD:

Restrictive Dermopathy

ROS:

Reactive Oxygen Species

RTS:

Rothmund-Thomson Syndrome

TCR:

Transcription-Coupled Repair

TTD:

Trichothiodystrophy

WS:

Werner Syndrome

WT:

Wild Type

XP:

Xeroderma Pigmentosum

XPO1:

Exportin-1

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Funding

Bilateral Agreement CNR (Italy)/CINVESTAV (Mexico), Grant/Award Number: CNR2018/4. Geriatric National Institute, Mexico, Grant/Award Number: INGER-DICRECITES-008-2018.

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Authors and Affiliations

  1. Department of Genetics and Molecular Biology, Center of Research and Advanced Studies (CINVESTAV-IPN), Mexico City, Mexico

    Ian García-Aguirre, Feliciano Monterrubio-Ledezma & Bulmaro Cisneros

  2. Department of Neurodevelopment and Physiology, Institute of Cellular Physiology, National Autonomous University of Mexico (UNAM), Mexico City, Mexico

    Alma Alamillo-Iniesta & Susana Castro-Obregón

Authors
  1. Ian García-Aguirre
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  2. Feliciano Monterrubio-Ledezma
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  3. Alma Alamillo-Iniesta
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  4. Susana Castro-Obregón
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  5. Bulmaro Cisneros
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Corresponding author

Correspondence to Bulmaro Cisneros .

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Editors and Affiliations

  1. Basic Sciencies Division, National Institute of Geriatrics, Ciudad de México, Mexico

    Juan Carlos Gomez-Verjan

  2. Instituto Nacional de Geriatría (INGER), Ciudad de México, Mexico

    Nadia Alejandra Rivero-Segura

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García-Aguirre, I., Monterrubio-Ledezma, F., Alamillo-Iniesta, A., Castro-Obregón, S., Cisneros, B. (2020). Molecular Basis of Progeroid Diseases. In: Gomez-Verjan, J., Rivero-Segura, N. (eds) Clinical Genetics and Genomics of Aging. Springer, Cham. https://doi.org/10.1007/978-3-030-40955-5_10

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