The genetics of cystic fibrosis

Presentation Outline Cystic Fibrosis (CF) Screens/diagnostics 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 (CF) Screens/diagnostics Disease heritability Gene & mutations Genotype-phenotype Outlook & discussion

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

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

Hallmarks of CF Very salty-tasting skin Appetite, but poor growth & weight gain Coughing, wheezing & shortness of breath Lung infections, e.g. pneumonia/bronchitis

Clinical Aspects Cystic fibrosis affects the entire body Lungs and sinuses GI, liver and pancreas Endocrine system Reproductive system

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.

Epidemiology CF is a rare disease CF is a disease of Caucasians. 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%

Heritability 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 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.

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.

CFTR Mutations 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 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

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?

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.

Further Reading The Cystic Fibrosis Foundation http://www.cff.org 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

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