Transcript Case Study 3: Hutchinson-Gilford’s Progeria Syndrome

Case Study 3: Werner’s Syndrome a progeriac 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, pcd)
Context: George Martin, 1978
‘Genetic Syndromes in Man with Potential Relevance
to the Pathology of Aging’
< 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
Aging a multigene process
10 genetic diseases that mimic aging process—but only in part
Appears
Chromosomal aneuploides Down’s syndrome
Birth
Dementia, cataracts, diabetes, hair graying, cancer
Known single mutant geneWerner’s syndrome
Skin ‘thinning’, Hair graying and loss, atherosclerosis,
Cataracts, cancer diabetes, osteoporosis
Autosomal recessive
Known single gene
Hutchinson-Gilford’s Progeria
Skin ‘thinning’ hair loss, atherosclerosis, osteoporosis,
Hypertension
Autosomal dominant
In 20’s
Helicase
Birth/1yr
Lamin A
(LMNA
Gene)
Werner’s Syndrome
www.pathology.washington.edu/werner/
Werner’s 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 20’s,
Major cause of death—heart attack in mid 40s
Cells of Progeria and WS
Cell Culture
What do cells need to proliferate?
When compare fibroblasts of child with Progeria and their parent
Child’s cells are ‘older’ in terms of replication
Fibroblasts
‘normal cells’ divide ~12 to 24 hours
Divide approx 50times in culture
Progeriac Fibroblasts:
Rarely ever double
Few cell generations before death
Note: Often ‘Progeriac’ used to describe any premature aging
as well as the specific disorder Hutchinson Gilford Progeria
Why do we age?/How how do we age?
Short answer: Don’t know
The 3 R’s: Mutation effecting DNA reading, replicating or repair
3 Hypotheses for Aging:
1) Free Radical Theory: Aging due to accumulation of
damage from free radicals
2) Telomere Theory: Chromosome ends shorten with divisions
Cause of Werner’s syndrome
3) Helicase defect: Mutation Chromosome 8 in WRN gene
all 35 known mutations result in truncated protein
all ‘remove’ nuclear targeting sequence
different mut’s associated with different cancers
Case Study Focuses
Cell death: damage and apoptosis
Telomeres and replication
Cell Cycle and its regulation