The genetics of cystic fibrosis
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Presentation Outline
Get the article on ERES: McKone EF, Emerson SS, Edwards KL, Aitken ML.
Effect of genotype on phenotype and mortality in cystic fibrosis: a
retrospective cohort study. Lancet. 2003 May 17;361(9370):1671-6.
I.
II.
III.
IV.
V.
VI.
Cystic Fibrosis (CF)
Screens/diagnostics
Disease heritability
Gene & mutations
Genotype-phenotype
Outlook & discussion
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Cystic Fibrosis
"Woe is the child who tastes salty from a kiss on
the brow, for he is cursed, and soon must die.“
-Northern European Folklore
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Notable History
1838
Carl von Rokitansky’s
autopsy of infant with
Meconium peritonitis
1905
Austrian Karl Landsteiner
describes Meconium ileus
1938
Cystic fibrosis disease
identified by American
Dorothy H. Andersen
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Hallmarks of CF
Very salty-tasting skin
Appetite, but poor
growth & weight gain
Coughing, wheezing
& shortness of breath
Lung infections, e.g.
pneumonia/bronchitis
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Clinical Aspects
Cystic fibrosis affects the entire body
• Lungs
and sinuses
• GI, liver and pancreas
• Endocrine system
• Reproductive system
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The Sweat Test
Measures the concentration of chloride and
sodium that is excreted in sweat.
Two reliable positive results on two separate
days is diagnostic for CF.
Clinical presentation, family history and patient
age must be considered to interpret the results.
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Epidemiology
CF is a rare disease
Approximately 30,000 in the U.S. people have CF
Over 10 million Americans are unknowing carriers.
Around 2,500 children with CF are born each year.
CF is a disease of Caucasians.
Group
Incidence
Carriers
Delta F508
Caucasians
1 / 3,300
1 / 29
70%
Hispanics
1 / 9,000
1 / 46
46%
African Americans
1 / 15,300
1 / 60
48%
Asian Americans
1 / 32,100
1 / 90
30%
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Heritability
CF is a hereditary disease.
Unaffected parents can have
children with CF.
Males and females are equally
likely to be diagnosed.
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Mapping the gene for CF
Gene linkage studies were able to
map the mutation to chromosome 7.
Classical genetics techniques were
not able to accurately pinpoint the
mutated gene.
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Mapping the gene for CF
1989: Lap-Chee Tsui, at the Hospital for Sick Children in
Toronto, clones the CFTR gene. Victory tastes sweet.
Chromosome walking and jumping techniques were used
to identify and sequence the 180,000 bp gene.
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The ΔF508 Mutation
A 3 base pair deletion called ΔF508 is the most
common mutation causing cystic fibrosis
The mutation results in the deletion of a single
amino acid (Phe) at position 508.
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Benefits of ΔF508
The ΔF508 mutation most likely occurred
over 50,000 years ago in Northern Europe.
Individuals with two copies of ΔF508 get cystic
fibrosis and often cannot reproduce.
Having one copy of ΔF508 reduces water loss
during cholera, greatly increasing the chance of
survival.
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The Function of CFTR
CFTR encodes a 170 kDa, membrane-based
protein with an active transport function
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From Mutation to Disease
The mutant form of CFTR
prevents chloride transport,
causing mucus build-up
Mucus clogs the airways
and disrupts the function of
the pancreas & intestines.
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CFTR Mutations
Over 1,000 mutations in
CFTR have been found.
ΔF508 accounts for just
70% of CF cases.
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5 Classes of CFTR Mutations
CF Mutations can be classified by the effect they
have on the CFTR protein.
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5 Classes of CFTR Mutations
I
II
III
IV
V
Defective
Defective
Defective
Defective
Reduced
Production
Processing
Regulation
Conductance
Amounts
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Genotype Class and Mortality
Mutation class can affect disease mortality.
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Genotype and Phenotype
Clinical phenotypes can vary widely across mutations
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Newborn Screening
Infants can easily be diagnosed with a blood test
Elevated levels of trypsinogen indicate CF
Screening programs identify 10% of cases at birth
Most hospitals do not screen for CF at birth.
Should they?
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Genetic Carrier Testing
Tests for common CF mutations
are available.
The type of defective CF gene
can affect the type of CF
symptoms.
However, genetic testing cannot
fully determine how severe a
person's CF will be in advance.
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Further Reading
McKone et al. Effect of genotype on phenotype and mortality in cystic
fibrosis: a retrospective cohort study. Lancet 2003.
The Cystic Fibrosis Mutation Database
http://www.genet.sickkids.on.ca/cftr
The Cystic Fibrosis Foundation
http://www.cff.org
Cystic Fibrosis on Wikipedia
http://en.wikipedia.org/wiki/Cystic_fibrosis
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Image Credits
http://en.wikipedia.org/wiki/Cystic_fibrosis and /wiki/CFTR_%28gene%29
http://www.cff.org
http://adam.about.com/encyclopedia/18135.htm
http://hipusa.com/eTools/webmd/A-Z_Encyclopedia/cysticfibrosisbasics.htm
http://prometheus.mse.uiuc.edu/research/cysticFibrosis/cysf.html
http://www.medicalprogress.org/news/newsarchive.cfm?news_id=237
http://www.musicunites.com/CF.htm
http://www.meddean.luc.edu/lumen/meded/elective/pulmonary/cf/cf_f.htm
http://learn.genetics.utah.edu/units/disorders/whataregd/cf/
http://www.sixtyfiveroses.com
http://www.cf.ac.uk/biosi/staff/jacob/teaching/ionchan/ionchan2.html
http://www.ambrygen.com/ts/ts.htm
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