Genotype and phenotype in cystic fibrosisPresentation Transcript
The genetics of cystic fibrosis Presented by Dan Koboldt [email_address] See slide 24 for image credits
Cystic Fibrosis (CF)
Gene & mutations
Outlook & discussion
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.
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
Austrian Karl Landsteiner
describes Meconium ileus
1938 Cystic fibrosis disease identified by American Dorothy H. Andersen 1838 Carl von Rokitansky’s autopsy of infant with Meconium peritonitis
Hallmarks of CF
Very salty-tasting skin
Appetite, but poor growth & weight gain
Coughing, wheezing & shortness of breath
Lung infections , e.g. pneumonia/bronchitis
Cystic fibrosis affects the entire body
Lungs and sinuses
GI, liver and pancreas
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.
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 . 30% 1 / 90 1 / 32,100 Asian Americans 48% 1 / 60 1 / 15,300 African Americans 46% 1 / 46 1 / 9,000 Hispanics 70% 1 / 29 1 / 3,300 Caucasians Delta F508 Carriers Incidence Group
CF is a hereditary disease.
Unaffected parents can have children with CF.
Males and females are equally likely to be diagnosed.
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.
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.
The ΔF508 Mutation
The mutation results in the deletion of a single
amino acid (Phe) at position 508.
A 3 base pair deletion called ΔF508 is the most common mutation causing cystic fibrosis
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.
The Function of CFTR
CFTR encodes a 170 kDa, membrane-based
protein with an active transport function
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.
Over 1,000 mutations in
CFTR have been found.
ΔF508 accounts for just
70% of CF cases.
5 Classes of CFTR Mutations
CF Mutations can be classified by the effect they
have on the CFTR protein.
5 Classes of CFTR Mutations I Defective Production II Defective Processing III Defective Regulation IV Defective Conductance V Reduced Amounts
Genotype Class and Mortality
Mutation class can affect disease mortality .
Genotype and Phenotype
Clinical phenotypes can vary widely across mutations
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.
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.
The Cystic Fibrosis Foundation
Cystic Fibrosis on Wikipedia
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
http://en.wikipedia.org/wiki/Cystic_fibrosis and /wiki/CFTR_%28gene%29