Ellen M. Wijsman

Research Program:

I am not currently working on this project, but have left the page up since it was a neat project, has a link to a very interesting pedigree, and leaves some unanswered questions that maybe we will eventually get around to addressing.

Werner's syndrome

Werner's syndrome is an autosomal recessive disorder which is characterized by the premature occurrence of age-related diseases and the premature appearance of some of the physical features of normal aging. Subjects develop a striking array of age-related degenerative and proliferative disorders early in life. These include some of the most significant age-related diseases of man such as arteriosclerosis, a variety of benign and malignant neoplasms, diabetes mellitus, osteoporosis, and ocular cataracts. Other features innclude cutaneous atrophy, short stature, graying or loss of hair, hypogonadism, altered skin pigmentation, high-pitched voice, hyperkeratosis, tight skin, a bird-like facies, cutaneous ulcers of the legs, telangiectasia, and a shortened life expectancy. Onset of at least some of the symptoms is usually noted after adolescence although shortened stature may indicate some undefined alteration in development.

We cloned the Werner's syndrome gene (WRN). This is the first human gene implicated in aging to be identified. To clone this gene, we used a combination of homozygosity mapping, linkage disequilibrium mapping and haplotype analysis to obtain fine-scale localization, followed by construction of high resolution radiation hybrid and physical maps of the gene region, and identification and sequencing of candidate genes cloned from the region. The WRN gene is a DNA helicase, with homology to the E. coli Rec Q gene (and other helicases). There is a single, predominant mutation in the Japanese population, accounting for 60-70% of Werner's syndrome disease alleles in that population. A number of other mutations have also been identified from both the Japanese population, and various European and other populations.

A few of the publications most relevant to the approaches we used in leading up to identification of this gene are the following:

Yu CE, Oshima J, Goddard KAB, Miki T, Nakura J, Ogihara T, Fraccaro M, Puissan C, Martin GM, Schellenberg GD, Wijsman EM (1994) Linkage disequilibrium and haplotype studies of chromosome 8p 11.1-21.1 markers and Werner's syndrome. Am J Hum Genet 55:356-364.
Goddard KAB, Yu CE, Oshima J, Miki T, Nakura J, Piussan C, Martin GM, Schellenberg GD, Wijsman EM (1996) Toward localization of the Werner syndrome gene by linkage disequilibrium and ancestral haplotyping: lessons learned from analysis of 35 chromosome 8p11.1-21.1 markers. Am J Hum Genet 58:1286-1302. Note: this paper contains the first published report and a figure of the JV pedigree - a pedigree with an interesting pattern of complex inbreeding loops that is of interest to the development of methodology for analysis of complex pedigrees. You can find a picture of this pedigree on the Genepi web page. If you use the pedigree as an example in methodological work, please cite the paper by Goddard et al.
Yu CE, Oshima J, Fu YH, Hisima F, Wijsman EM, Martin GM, Mulligan J, Schellenberg GD (1996) Positional cloning of the Werner's syndrome gene. Science 272:258-262.

More information can be found on the Werner syndrome home page.