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Genetic instability syndromes with progeroid features

Genetische Instabilitätssyndrome mit progeroiden Manifestationen

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Abstract

We discuss examples of the rare human genetic instability syndromes as they present themselves at the chromosome, telomere, and nuclear envelope level. Destabilization of the nuclear envelope due to mutations in the Lamin A/C gene lead to global impairments of the chromatin structure and gene expression with the fatal consequences observed in the Hutchinson-Gilford juvenile progeria syndrome. Patients with Dyskeratosis congenita have defective telomerase function. These patients exhibit a number of progeroid features, suggesting a causal connection between short telomeres and premature ageing. The most prominent example of the chromosomal instability syndromes is the Werner adult progeria syndrome where impaired helicase and exonuclease functions cause a multitude of (albeit superficial) similarities with the normal ageing process. A less well-know example is Fanconi anemia (FA) a multisystem disorder caused by biallelic mutations in one of at least 13 different genes which include the BRCA2 breast cancer gene. Unlike cells from any other human disorder, FA cells are uniquely sensitive to oxidative stress. In a situation of defective DNA repair, oxidative stress leads to accumulation of (unrepaired) DNA damage. Oxidative stress is the likely culprit of bone marrow failure, risk of neoplasia, and features of premature ageing in FA, rendering this rare disease into the only known human model of the free radical theory of ageing.

Zusammenfassung

Menschliche Krankheitsbilder, die mit genetischer Instabilität einhergehen, manifestieren sich u. a. auf der Ebene der Chromosomen, Telomere und der Kernhülle. Mutationen im Lamin A/C-Gen führen zur Destabilisierung der Kernhülle und damit zu globalen Veränderungen der Zellkernorganisation und der Genexpression. Dies erklärt die Vielzahl der Defekte bei der Hutchinson-Gilford-Progerie. Patienten mit Dykeratosis congenita zeigen ebenfalls vorzeitige Alterungserscheinungen, die aufgrund entsprechender Mutationen mit eingeschränkter Telomerase- Funktion und überdurchschnittlich verkürzten Telomeren in Verbindung gebracht werden. Das bekannteste Beispiel der chromosomalen Instabilitätssyndrome ist das Werner-Syndrom dem biallelische Mutationen in einem Gen mit sowohl Helikaseals auch Exonuklease-Funktion zugrunde liegen. Allerdings zeigt die progeroide Symptomatik des Werner-Syndroms nur oberflächliche Übereinstimmung mit demnormalen Alterungsprozess. Das am wenigsten bekannte Chromosomenbruchsyndrom ist die Fanconi-Anämie, welche durch biallelische Mutationen in einem von zumindest 13 verschiedenen DNA-Reparaturgenen, darunter das BRCA2-Gen, verursacht wird. Die Fanconi-Anämie ist die einzige Erkrankung des Menschen, deren Zellen eine konstitutionelle Überempfindlichkeit gegen oxidativen Stress aufweisen. Die Validität der freien Radikal-Theorie des Alterns lässt sich daher anhand der Fanconi-Anämie erstmals auch am Menschen überprüfen.

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Authors and Affiliations

  1. University of Würzburg, School of Medicine, Department of Human and Medical Genetics, Biozentrum, am Hubland, 97074, Würzburg, Germany

    K. Neveling, A. Bechtold MD & H. Hoehn MD

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  1. K. Neveling
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  2. A. Bechtold MD
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  3. H. Hoehn MD
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Correspondence to H. Hoehn MD.

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Neveling, K., Bechtold, A. & Hoehn, H. Genetic instability syndromes with progeroid features. Z Gerontol Geriat 40, 339–348 (2007). https://doi.org/10.1007/s00391-007-0483-x

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  • DOI: https://doi.org/10.1007/s00391-007-0483-x

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