The Principles of Clinical Cytogenetics - Extra Materials - Springer

Chromosome Instability 355
Fig. 4. Chromosome 1 multiradial configuration from a patient with ICF syndrome. Some stretching of the
pericentromeric heterochromatin can also be seen. (Courtesy of Dr. Jeffrey Sawyer.)
particularly of chromosomes 1, 9, and 16, are commonly seen in metaphases of most (80%) of RS
patients (see Fig. 5). Other cytogenetic abnormalities such as aneuploidy with random chromosome
loss, micronuclei, and abnormal nuclear morphology are also observed. Barbosa et al. (45) demonstrated
asynchronous replication of homologous α-satellite DNA, more evident in chromosomes 1, 9,
and 16 in RS cells. This asynchrony, in turn, prevents the establishment of proper cohesion between
sister chromatid heterochromatin, leading to chromosome lag and aneuploidy. RS has been interpreted
as a human mitotic mutation syndrome, which leads to secondary developmental defects. Cytogenetic
analysis by solid staining or C-banding has been used in the diagnosis of RS.
Werner Syndrome
Werner syndrome (WS) is a human premature aging syndrome manifested by sclerodermalike
skin changes, especially in the extremities. Wizened and prematurely aged faces are often observed
in individuals affected with WS (see Fig. 6). The most consistent feature of WS is cataracts. Variable
features include diabetes mellitus, hypogonadism, osteoporosis, atherosclerosis, and an increased
incidence of neoplasia. Malignant sarcomas, meningiomas, and carcinomas are seen in approximately
10% of WS patients. Cancer is the leading cause of death of WS patients. The prevalence of carriers
is reported to be as high as 1/150 to 1/200 (47).
The frequency of spontaneous chromosome damage in WS is not as striking as it is in other chromosome
instability syndromes. A variety of somatic chromosome rearrangements was noted in cultured
skin fibroblasts from WS patients. Variegated translocation mosaicism (VTM) has been used to
designate the pattern of pseudodiploidy with multiple, variable, and stable chromosome aberrations
noted in WS cells.
Skin fibroblast lines established from WS have a diminished in vitro life-span. WS cells usually
achieve only about 20 population doublings in contrast with the approximately 60 doublings seen in
normal control cells. Studies of cultured cells from an obligate heterozygote revealed that these cells
exited the cell cycle at a faster rate than did normal cells. Wyllie et al. demonstrated that forced expression
of telomerase in WS fibroblasts confers an extended cellular life-span. Telomerase activity and
telomere extension is sufficient to prevent accelerated cell aging in WS fibroblast cultures (48).
The gene responsible for WS (WRN, with a total of 35 exons), was identified by positional cloning
(49). WRN is a DNA helicase belonging to the RecQ family and is an exonuclease that participates in