From Premature Gray Hair to Helicase – Werner Syndrome: Implications for Aging and Cancer

Details:

Gann Monograph on Cancer Research No 49
M Goto and RW Miller (eds)
Published by by Japan Scientific Societies Press and S Karger AG, Basel (2001)
ISBN:  3-8055-7158-5.  165 pages plus index.
RRP:  US$243.50


In the history of biological research, and of medicine, a grand recurring theme is that the study of mutants has provided many major insights.  The ramifications of mutations in the WRN gene, which are responsible for most cases of Werner syndrome, include the early onset of age-related diseases such as atherosclerosis, osteoporosis, cataracts, type II diabetes mellitus and cancers.  Therefore many diseases that have a major impact in Western countries can potentially be illuminated by a study of this uncommon autosomal recessive condition.

Werner syndrome itself has an interesting history.  It was described in 1904 by a German medical student, Otto Werner. The disease occurs most frequently in Japan, where two WRN mutations account for the majority of cases. The most common of these is thought to have arisen in a member of a Samurai clan. Japanese clinicians have assembled large and informative case series.  A landmark paper on the clinical features, co-authored by George Martin who is a contributor to this book, was published in 1966. The WRN gene was identified by a group led by Gerry Schellenberg in Seattle in 1996. From the viewpoint of understanding the molecular details of Werner syndrome, however, this was just the beginning of the story. 

The gene was found entirely on the basis of the knowledge of its approximate position on the long arm of chromosome 8 (ie by positional cloning), without any knowledge of its function.  When the gene was identified, the function did not suddenly become clear.  Some features of the encoded protein provided a clue, however, that it is almost certainly involved in normal processing of DNA, which underscores the importance of DNA damage in ageing and in cancer. 

At 165 pages, this is not an excessively thick book, but it is a fairly comprehensive summary of knowledge about Werner syndrome.  The 16 chapters of this book on Werner syndrome have a broad scope. There are two main sections, the first of which contains a brief history of research on this syndrome, and chapters on epidemiology, pathology, and clinical manifestations, with particular emphasis on features of premature ageing, dermatological features, atherosclerosis, nervous system disorders, and cancer (especially thyroid carcinoma and osteosarcoma).  There is not a separate chapter on the ocular manifestations, although Werner discovered the syndrome while on rotation in an ophthalmology clinic.  The second section contains chapters on cellular and molecular studies of Werner syndrome. 

Appropriately, the chapters on epidemiology, clinical features and pathology mostly have Japanese authors. In addition to his contributions to other chapters, Makoto Goto, a Tokyo rheumatologist who has worked extensively on case collection and clinical studies, has written a chapter that puts Werner syndrome in the context of other premature ageing syndromes.  The link between the clinical section of the book and the section on cellular and molecular changes is provided by Ray Monnat’s thoughtful chapter which speculates on possible ways in which the WRN mutation may lead to the clinical manifestations, especially cancer. There are chapters on the chromosomal changes, the cellular phenotype, and on the function of the WRN protein. There is a chapter on WRN homologues in nonhuman systems, including yeast and even bacteria. The class of proteins to which WRN belongs is in fact named after a bacterial enzyme, RecQ, that is involved in unwinding helical DNA.  As an aside, it is pertinent to note here that Werner made the remarkably insightful observation that the syndrome he described was most similar to one published by Rothmund in 1868, the features of which include proneness to osteosarcoma. Ninety-five years later, Yasuhiro Furuichi and colleagues found that a subset of Rothmund-Thomson cases have a mutation in another RecQ helicase gene.

The chapters have been thoroughly edited, so that they have a fairly uniform style and are all easy to read. This has not stymied the appropriate expression of various viewpoints by different authors. The reader will readily pick up differences of opinion, for example, regarding the extent to which this syndrome can be used as a model for normal ageing.

I must confess to a partiality to the WRN gene.  My laboratory group was involved very peripherally in the race to clone it, and we have an ongoing interest in investigating its functions.  The reader may therefore wish to discount some of my enthusiasm for this book, but I think that there is something for everyone here.  The richness of its progression from clinical features to emerging molecular details makes it easy to agree with the first sentence of the preface: “If you love the diversity of medicine you should enjoy this book”.

R Reddel
Children’s Medical Research Institute
Westmead, NSW

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