The genetics of cystic fibrosis

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Transcript The genetics of cystic fibrosis

The genetics of cystic fibrosis


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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 .


. 2003 May 17;361(9370):1671-6.







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


Carl von Rokitansky’s autopsy of infant with Meconium peritonitis


Austrian Karl Landsteiner describes Meconium ileus


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


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 .


Caucasians Hispanics African Americans Asian Americans


1 / 3,300 1 / 9,000 1 / 15,300 1 / 32,100


1 / 29 1 / 46 1 / 60 1 / 90

Delta F508

70% 46% 48% 30% 8


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


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 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.


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


Defective Processing


Defective Regulation


Defective Conductance


Reduced Amounts 18

Genotype Class and Mortality

Mutation class can affect disease mortality .


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?


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




The Cystic Fibrosis Mutation Database The Cystic Fibrosis Foundation

Cystic Fibrosis on Wikipedia 23

Image Credits and /wiki/CFTR_%28gene%29