Case Study 3: Werner

1
Case Study 3 Werners Syndrome a progeric disease
Cell Division Cell Cycle
Aging
What mechanisms control the proliferation of
cells?
What governs the life span of an organism?
Cell death as a necessary and important part of
development Apoptosis (programmed cell death)
2
Context George Martin, 1978
Genetic Syndromes in Man with Potential
Relevance to the Pathology of Aging
lt 7000 genes involved in degenerative processes
associated with aging
Between 70 and 7 genes control processes having
large impact on senescence
What is cell senescence?Divide certain of
times then enter G0 and eventually die
3
Aging a multigene process
10 genetic diseases that mimic aging processbut
only in part
Chromosomal aneuploides? Downs syndrome
Dementia, cataracts, diabetes, hair graying,
cancer
Known single mutant gene?Werners syndrome
Skin thinning, Hair graying and loss,
atherosclerosis, Cataracts, cancer diabetes,
osteoporosis
Unknown but thought to be single gene?
Hutchinson-Gilfords Progeria
Skin thinning hair loss, atherosclerosis,
osteoporosis, hypertension
4
Werners Syndrome
www.pathology.washington.edu/werner/
5
Werners history
Named for C. W. Otto Werner (1879-1936) Rural
doctor, medical officer in German Navy WWI Rare
autosomal recessive disease Approx 1 in 200
people carriers for defective gene Approx 3 in
1,000,000 people have the disease (Slightly
higher percentage in Japan) Onset of symptoms
early to mid 20s, Major cause of deathheart
attack in mid 40s
6
Cells of Progeria and WS
Cell Culture What do cells need to proliferate?
When compare fibroblasts of child with Progeria
and their parent Childs cells are older in
terms of replication
Progeric Fibroblasts Rarely ever double Few
cell generations before death
Note Often Progeric used to describe any
premature aging as well as the disease Hutchinson
Gilford Progeria
7
Why do we age?/How how do we age?
Short answer Dont know
The 3 Rs Mutation effecting DNA reading,
replicating or repair
Hypotheses for Aging
Free Radical Theory Aging due to accumulation of
damage from free radicals
Telomere Theory Chromosome ends shorten with
divisions
Cause of Werners syndrome
Helicase defect Mutation Chromosome 8 in WRN
gene all 35 known mutations result in truncated
protein all remove nuclear targeting
sequence different muts associated with
different cancers
8
Case Study Focuses
Cell death damage and apoptosis
Telomeres and replication
Cell Cycle and its regulation