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Werner and Hutchinson–Gilford progeria syndromes: mechanistic basis of human progeroid diseases

Nature Reviews Molecular Cell Biology volume 8, pages 394–404 (2007)Cite this article

Key Points

  • Two of the best characterized progeroid syndromes are Werner syndrome and Hutchinson–Gilford progeria syndrome (HGPS). The genes targeted for mutation in these diseases (WRN and LMNA, respectively) have been identified.

  • WRN encodes a RecQ helicase and functions in homology-dependent recombination and telomere metabolism. Defective regulation of either of these fundamental nuclear processes could underlie disease.

  • LMNA encodes A-type nuclear lamins, which are targets for mutations in several human genetic diseases, known as laminopathies.

  • Specific mutations in LMNA, many of which affect farnesylation of the C terminus of lamin A, function dominantly to give rise to HGPS. Farnesylation inhibitors effectively suppress disease phenotypes in mouse models of HGPS.

  • It remains unclear whether common mechanisms underlie the progeroid syndromes and whether these mechanisms contribute significantly to the normal ageing process.

Abstract

Progeroid syndromes have been the focus of intense research in part because they might provide a window into the pathology of normal ageing. Werner syndrome and Hutchinson–Gilford progeria syndrome are two of the best characterized human progeroid diseases. Mutated genes that are associated with these syndromes have been identified, mouse models of disease have been developed, and molecular studies have implicated decreased cell proliferation and altered DNA-damage responses as common causal mechanisms in the pathogenesis of both diseases.

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Figure 1: WRN function and disease pathogenesis.
Figure 2: The maturation of lamin A.
Figure 3: Model for the pathogenesis of HGPS in the presence of progerin.

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Acknowledgements

B.A.K. was supported in part by a National Institute of General Medical Science grant. Lamin-related research in the laboratory of B.K.K. is supported by a National Institutes of Health grant. This work was supported by grants from National Cancer Institute and the Nippon Boehringer Ingelheim Virtual Research Institute on Aging to R.J.M.Jr.

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Authors and Affiliations

  1. Department of Biochemistry, University of Washington, Seattle, 98195, Washington, USA

    Brian A. Kudlow & Brian K. Kennedy

  2. Department of Pathology, University of Washington, Seattle, 98195, Washington, USA

    Raymond J. Monnat Jr

  3. Department of Genome Sciences, University of Washington, Seattle, 98195, Washington, USA

    Raymond J. Monnat Jr

  4. Departments of Molecular and Cellular Biology Program, University of Washington, Seattle, 98195, Washington, USA

    Brian A. Kudlow

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  1. Brian A. Kudlow
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  2. Brian K. Kennedy
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  3. Raymond J. Monnat Jr
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Corresponding authors

Correspondence to Brian K. Kennedy or Raymond J. Monnat Jr.

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The authors declare no competing financial interests.

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DATABASES

OMIM

Ataxia-telangiectasia

Down syndrome

Hutchinson–Gilford progeria syndrome

Werner syndrome

FURTHER INFORMATION

Ray Monnat's laboratory

Leiden Muscular Dystrophy pages

Locus-Specific Mutational Database

Online Mendelian Inheritance in Man

SNP linked to WRN

The LMNA mutation database

Werner Syndrome International Registry

Glossary

RecQ helicase

A protein with a domain that contains sequence and structural homology to the Escherichia coli RecQ helicase. Human RecQ helicase proteins include WRN, BLM and REQ4.

Homology-dependent recombination

A potentially error-free DNA-repair pathway in which DNA double-strand breaks are repaired by limited DNA synthesis off a second, undamaged DNA molecule (for example, a sister chromatid) followed by resolution and religation of strand breaks.

Senescence

A state of permanent cell-cycle exit that often occurs as a result of a cell exhausting its replicative potential. It can also result from cellular stresses or activation of oncogenes.

Non-homologous DNA-end joining

A DNA-repair pathway that can operate in all phases of the cell cycle and that does not require the presence of a homologous DNA-repair template to repair DNA double-strand breaks.

Base-excision repair

A DNA-repair pathway that selectively identifies and replaces single DNA bases that have been chemically damaged.

Mesenchymal cell lineage

Cell lineages that are derived from the mesodermal germ layer. Includes many cell types that are found in connective tissue and other supporting, conducting or blood-forming lineages of the body.

Nuclear lamina

The proteinacious meshwork that underlies the inner nuclear membrane.

Neomorphic allele

An allele of a gene that confers to the encoded gene product a new activity not normally found in the product encoded by the wild-type allele.

Hypermorphic allele

An allele of a gene that confers to the encoded gene product an increase in the activity that is normally associated with the product encoded by the wild-type allele.

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Kudlow, B., Kennedy, B. & Monnat, R. Werner and Hutchinson–Gilford progeria syndromes: mechanistic basis of human progeroid diseases. Nat Rev Mol Cell Biol 8, 394–404 (2007). https://doi.org/10.1038/nrm2161

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