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HUNTINGTON'S DISEASE
AS AN EXAMPLE
• Inheritance pattern - dominant autosomal
• Entirely penetrant and fatal
• Frequency - about 1/10,000 live births
• Late onset - age 35 to 45
• No biochemical defect known, until very
recently
• No methods of treatment
• Because of late onset, many have children
before symptoms appear
Influence of the Wexler family
Hereditary Disease
Foundation
Families with a history of
Huntington's disease
• Indiana University maintains a
National Research Roster for
Huntington's Patients
• Large family with a history of
Huntington's disease discovered
living on shore of lake Maracaibo in
Venezuela
For both families with a
history of Huntington's
disease:
• Blood samples taken from each
member
• Permanent cell lines established
• Each family member analyzed by a
neurologist for disease symptoms
• Paternity verified
Objective: Finding a probe
that uncovered an RFLP
that was linked to
Huntington's disease.
1981 - Gusella's group
started with a group of
anonymous probes that
uncovered RFLPs - very few
available.
They were incredibly lucky -
the 12th probe they tried
-called G8 - indicated
linkage.
• Disease associated with the A
haplotype in the American family
and the C haplotype in the
Venezuelan family.
LOD Scores
D788
7q31
met
Step 1: Chromosome walking to make a contig
met
probe for 3rd step
probe for 2nd step
In the case of the CF gene, 7
jumps of 50 to 75 kb were
made with each arrival point
then serving as a new origin
for chromosome walking.
Step 2: Identification of candidate genes: Zoo blot
A C
B D
H M D H M D H M D H M D
L B T L B T L B T L B T
L = lung mRNA
B = brain mRNA
T = testis mRNA
• The map position agreed with the
linkage data
• The probe had a CpG island at the
start of the coding sequence
• The gene was detected in Northern
blots using RNA extracted from the
"correct" tissue, in this case cultured
epithelial (sweat gland) cells
Diagnostic tests are
available, but extensive
testing is necessary
because there are so many
different mutations.
Since the function of the
gene is known, treatment
strategies can be devised.
Gene therapy
• Insert CFTR gene in adenovirus vector.
• Virus is used to infect CF patient by
inhalation.
• Virus inserts itself into lung cells,
where gene functions normally.
Why is disease so prevalent?