Transcript The genetics of cystic fibrosis
The genetics of cystic fibrosis
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Presentation Outline
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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.
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Cystic Fibrosis (CF) Screens/diagnostics Disease heritability Gene & mutations Genotype-phenotype Outlook & discussion 2
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 3
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 4
Hallmarks of CF
Very salty-tasting skin Appetite, but poor growth & weight gain Coughing, wheezing & shortness of breath Lung infections , e.g. pneumonia/bronchitis 5
Clinical Aspects
Cystic fibrosis affects the entire body • Lungs and sinuses • GI, liver and pancreas • Endocrine system • Reproductive system 6
The Sweat Test
Measures the concentration of chloride sodium that is excreted in sweat.
and 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. 7
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
Caucasians Hispanics African Americans Asian Americans
Incidence
1 / 3,300 1 / 9,000 1 / 15,300 1 / 32,100
Carriers
1 / 29 1 / 46 1 / 60 1 / 90
Delta F508
70% 46% 48% 30% 8
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 14
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. 15
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
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Defective Production
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Defective Processing
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Defective Regulation
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Defective Conductance
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Reduced Amounts 18
Genotype Class and Mortality
Mutation class can affect disease mortality .
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Genotype and Phenotype
Clinical phenotypes can vary widely across mutations 20
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. 22
Further Reading
McKone et al.
Effect of genotype on phenotype and mortality in cystic fibrosis: a retrospective cohort study
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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 23
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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