The genetics of cystic fibrosis

1
The genetics of cystic fibrosis

• Presented by Dan Koboldt
• dkoboldt_at_wustl.edu
• See slide 24 for image credits

2
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
17361(9370)1671-6.

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

3
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
4
Notable History

• 1905
• Austrian Karl Landsteiner
• describes Meconium ileus

1838 Carl von Rokitanskys autopsy of infant
with Meconium peritonitis
1938 Cystic fibrosis disease identified by
American Dorothy H. Andersen
5
Hallmarks of CF

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

6
Clinical Aspects

• Cystic fibrosis affects the entire body

• Lungs and sinuses
• GI, liver and pancreas
• Endocrine system
• Reproductive system

7
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.

8
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.

9
Heritability

• CF is a hereditary disease.
• Unaffected parents can have children with CF.
• Males and females are equally likely to be
  diagnosed.

10
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.

11
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.
12
The ?F508 Mutation
A 3 base pair deletion called ?F508 is the most
common mutation causing cystic fibrosis

• The mutation results in the deletion of a single
• amino acid (Phe) at position 508.

13
Benefits of ?F508

• The ?F508 mutation most likely occurred
• over 50,000 years ago in Northern Europe.

Individuals with two copies of ?F508 get cystic
fibrosis and often cannot reproduce. Having one
copy of ?F508 reduces water loss during cholera,
greatly increasing the chance of survival.
14
The Function of CFTR

• CFTR encodes a 170 kDa, membrane-based
• protein with an active transport function

15
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.
16
CFTR Mutations

• Over 1,000 mutations in
• CFTR have been found.
• ?F508 accounts for just
• 70 of CF cases.

17
5 Classes of CFTR Mutations

• CF Mutations can be classified by the effect they
  
• have on the CFTR protein.

18
5 Classes of CFTR Mutations
I Defective Production
II Defective Processing
III Defective Regulation
IV Defective Conductance
V Reduced Amounts
19
Genotype Class and Mortality

• Mutation class can affect disease mortality.

20
Genotype and Phenotype

• Clinical phenotypes can vary widely across
  mutations

21
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?

22
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.

23
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

24
Image Credits

• http//en.wikipedia.org/wiki/Cystic_fibrosis and
  /wiki/CFTR_28gene29
• http//www.cff.org
• http//adam.about.com/encyclopedia/18135.htm
• http//hipusa.com/eTools/webmd/A-Z_Encyclopedia/cy
  sticfibrosisbasics.htm
• http//prometheus.mse.uiuc.edu/research/cysticFibr
  osis/cysf.html
• http//www.medicalprogress.org/news/newsarchive.cf
  m?news_id237
• http//www.musicunites.com/CF.htm
• http//www.meddean.luc.edu/lumen/meded/elective/pu
  lmonary/cf/cf_f.htm
• http//learn.genetics.utah.edu/units/disorders/wha
  taregd/cf/
• http//www.sixtyfiveroses.com
• http//www.cf.ac.uk/biosi/staff/jacob/teaching/ion
  chan/ionchan2.html
• http//www.ambrygen.com/ts/ts.htm