Info

Halki Diabetes Remedy

New Treatment of Diabetes

Get Instant Access

Werner Syndrome as a Model of Human Aging

Raymond J. Monnat, Jr.

This chapter reviews clinical and basic science aspects of Werner syndrome (WS), a heritable human disease that displays features suggestive of premature aging. The resemblance of changes in WS to those observed in normal aging has long suggested WS may be a useful model in which to study the biology of aging and to identify mechanistic pathways responsible for age-associated diseases that are prevalent in WS patients and in normal aging such as atherosclerosis, neoplasia, diabetes mellitus, and osteoporosis. This chapter summarizes our understanding of the WS clinical phenotype. Current understanding of in vivo functions of the Werner syndrome protein is summarized, together with a discussion of how the loss of WRN function may promote disease pathogenesis in WS patients and in normal individuals. Subsections provide an historical overview of WS and WS research; a description of WS as a clinical disease entity, together with diagnostic criteria for WS; a discussion of the relationship of WS to normal aging; a summary of our current understanding of the WRN gene and the mutational basis for WS; a discussion of in vivo functions of the WS protein in human somatic cells, and how loss-of-function may be linked to disease pathogenesis; and an introduction to the more promising animal models of WS. A selection of the most useful additional resources on WS clinical medicine and biology are included to aid those interested in learning more about this fascinating and instructive human disease.

Introduction

Werner syndrome (WS) is an uncommon, autosomal recessive human disease that displays clinical features suggestive of premature aging. The initial description of WS was by Otto Werner, a German medical student, in 1904 (Werner, 1985). Werner saw a family in the north of Germany consisting of four siblings, ages 31 to 40, who shared common features including short stature, premature graying of the hair, bilateral cataracts, skin changes (hyperkeratosis, scleroderma-like changes and ulceration) that were most severe on the feet and ankles, atrophy of the extremities, and, in females, an early cessation of menstruation. He noted that one of the siblings, a 36-year-old male, gave ''the impression of extreme senility.'' Werner published these observations as part of his doctoral thesis, though he did not further study these or similar patients during the remainder of his career. He practiced general medicine in Eddelak, a small village on the North Sea near the Danish border, where he died in 1936 (Pehmoeller, 2001).

The eponym Werner's syndrome was first used in 1934 by Oppenheimer and Kugel in reporting findings in a patient (Oppenheimer and Kugel, 1934). Their paper, together with the more comprehensive study by Thannhauser (1945) of five additional cases, provided an accurate clinical description of WS that distinguished it from Rothmund (now Rothmund-Thomson) syndrome. The subsequent diagnosis of Werner syndrome in three affected, American-born sisters in a Japanese-American sibship seen in Seattle in the early 1960s led to further, detailed clinical and pathological characterization of Werner syndrome. Part of this characterization included a formal genetic analysis that firmly established an autosomal recessive mode of inheritance. These observations, together with a critical analysis of 122 additional cases, were published in 1966 (Epstein et al., 1966). This landmark paper remains readily accessible and a key source of information for investigators interested in WS (see Recommended Resources).

The modern clinical and biological investigation of WS has been an international effort. This reflects both the worldwide occurrence of WS (Goto, 1997) and early collaborative efforts by investigators in Japan (where WS is prevalent), the United States, and Western Europe to better define and understand the WS clinical phenotype and its underlying biology. The first major gathering of investigators to discuss this work was in Kobe, Japan, in 1982. This United States-Japan Cooperative Seminar on Werner's Syndrome and Human Aging was sponsored by the U.S. National Science Foundation and the Japan Society for the Promotion of Science. The proceedings of this workshop were subsequently published and represent an important first summarization of modern work to better define and understand WS (Salk et al., 1985). The published proceedings also include an important

Handbook of Models for Human Aging

Copyright © 2006 by Academic Press All rights of reproduction in any form reserved.

selection of published primary sources of information on WS (e.g., Epstein et al., 1966; Salk, 1982; Thannhauser, 1945) together with an edited translation of Otto Werner's thesis (Werner, 1985).

Several subsequent small workshops were sponsored by the U.S.-Japan Cooperative Cancer Research Program during the 1990s and led to further discussion of and interest in WS. These were part of a long-standing joint venture of the U.S. National Cancer Institute and the Japan Society for the Promotion of Science. Meetings held in 1994, 1996, and 1997 brought together investigators interested in WS as a cancer predisposition syndrome (1994), in clinical and biological aspects of WS (1996), and in the relationship of WS to other pediatric cancer syndromes (1997). The focus for these meetings broadened with a U.S.-Japan Workshop on Cancer in Human RecQ Helicase Gene Disorders (February 2002), the Keystone Symposia on DNA Helicases, Cancer and Aging (March 2002 and 2005), and a U.S. NIH-sponsored International Workshop on Werner Syndrome held in May 2003. Regrettably, the results of only one of these very productive workshops were captured in a meeting report (Bohr, 2003). The broader focus of these more recent meetings reflects the recognition that WS, Bloom syndrome, and Rothmund-Thomson syndrome are all human genetic instability/cancer predisposition disorders that result from mutations in different members of the five-member human RecQ helicase protein family (see later; Bachrati and Hickson, 2003; Opresko, Cheng et al., 2004).

Attempts were made in the 1980s and early 1990s to isolate or map the affected gene in WS. These approaches took advantage of potentially useful cellular phenotypes for complementation such as a severe in vitro cell proliferation defect and chromosomal instability, and the fact that WS is an autosomal recessive disease that likely resulted from a single gene defect. Attempts at functional complementation to identify the WRN gene were not successful for at least two important reasons: the scarcity and poor growth properties of primary cells from WS patients that were used as complementation hosts, and the large size of the WRN gene and the WRN open reading frame (see later). In contrast, linkage mapping using the then-new technique of homozygosity mapping was successful, and led in 1992 to assignment of the WRN locus to the proximal short arm of chromosome 8 in a region defined by five anonymous DNA markers (Goto et al., 1992). This initial linkage assignment, together with rapid maturation of methods for positional cloning in the early 1990s, led in 1996 to identification of the WRN locus and of unambiguous pathogenic mutations in the WRN gene of WS patients (Yu et al., 1996).

Successful positional cloning of the WRN gene with delineation of WS-associated WRN mutations and predictions of potential activities encoded in the WRN protein provided a powerful stimulus for subsequent work on WS. There was an immediate effort in several laboratories to confirm predicted biochemical activities, and then identify in vivo functions, of WRN. There was also renewed speculation on how the loss of WRN function could generate WS cellular and clinical phenotypes. Recent work has also begun to focus on genetic variation in the WRN gene, and the association of WRN mutations and polymorphisms with disease risk and disease pathogenesis in the general population. Each of these areas of investigation is discussed in greater detail below.

Werner Syndrome as a Clinical Disease Entity

The key clinical features of Werner syndrome were readily recognized by Otto Werner in the first patients he identified and described in 1904. These clinical signs or findings, outlined in Table 80.1, were subsequently confirmed and further elaborated by Oppenheimer and Kugel (1934), Thannhauser (1945), and Epstein et al.

TABLE 80.1 Diagnostic criteria for Werner syndrome

Consistent findings

♦ short stature

♦ bilateral cataracts

♦ premature graying and loss of scalp hair/eyebrows

♦ scleroderma-line skin changes

♦ parental consanguinity (3rd cousin or closer)

• laboratory

♦ elevated 24 hr urinary hyaluronic acid secretion Additional findings

• clinical findings

♦ voice changes

hypogonadism

• history or laboratory findings

♦ diabetes mellitus

♦ osteoporosis

♦ soft-tissue/tendon calcification

♦ premature atherosclerosis, myocardial infarction, stroke

Diagnostic likelihood of Werner syndrome

• definite: all of consistent clinical and history findings

• probable: short stature, bilateral cataracts and scleroderma-like skin changes, any two other clinical, history or laboratory findings

• possible: bilateral cataracts or scleroderma-like skin changes, any four other additional clinical, history or laboratory findings

• exclusion: onset of clinical or laboratory findings < age 10

(1966) in their analyses of WS patients and pedigrees. Among the most consistent and earliest of the features of WS to be observed are short stature, bilateral cataracts, the early graying and loss of hair, and scleroderma-like skin changes. All four features have been observed in all or nearly all patients (Epstein et al., 1966; Goto, 1997; Tollefsbol and Cohen, 1984). They appear de novo, and are not the secondary consequence of another systemic disease process, or the result of a primary endocrine deficiency or dysfunction syndrome. Each of these features or clinical signs of WS are discussed briefly, next, together with less consistently observed changes. This constellation of changes and the clinical appearance and progression of these changes have been used to develop criteria for the clinical diagnosis of WS.

Was this article helpful?

0 0
Diabetes Sustenance

Diabetes Sustenance

Get All The Support And Guidance You Need To Be A Success At Dealing With Diabetes The Healthy Way. This Book Is One Of The Most Valuable Resources In The World When It Comes To Learning How Nutritional Supplements Can Control Sugar Levels.

Get My Free Ebook


Post a comment