Koboldt_Cystic_Fibrosis_Genetics

8/7/2019 Koboldt_Cystic_Fibrosis_Genetics

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The genetics of cystic fibrosisThe genetics of cystic fibrosis

Presented by Dan KoboldtPresented by Dan Koboldt

[email protected]@wustl.edu

See slide 24 for image creditsSee slide 24 for image credits


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Presentation OutlinePresentation Outline

I.I. Cystic Fibrosis (CF)Cystic Fibrosis (CF)

II.II. Screens/diagnosticsScreens/diagnostics

III.III. Disease heritabilityDisease heritability

IV.IV. Gene & mutationsGene & mutationsV.V. GenotypeGenotype--phenotypephenotype

VI.VI. Outlook & discussionOutlook & 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.


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Cystic FibrosisCystic 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


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Notable HistoryNotable History

19051905

Austrian Karl LandsteinerAustrian Karl Landsteiner

describes Meconium ileusdescribes Meconium ileus

19381938

Cystic fibrosis diseaseCystic fibrosis disease

identified by Americanidentified by American

Dorothy H. AndersenDorothy H. Andersen

18381838

Carl von RokitanskysCarl von Rokitanskys

autopsy of infant withautopsy of infant with

Meconium peritonitisMeconium peritonitis


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Hallmarks of CFHallmarks of CF

Very saltyVery salty--tasting skintasting skin

Appetite, but poorAppetite, but poor

growth & weight gaingrowth & weight gain

Coughing, wheezingCoughing, wheezing

& shortness of breath& shortness of breath

Lung infectionsLung infections, e.g., e.g.

pneumonia/bronchitispneumonia/bronchitis


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Clinical AspectsClinical Aspects

Cystic fibrosis affects the entire bodyCystic fibrosis affects the entire body

Lungs and sinusesLungs and sinuses

GI, liver andGI, liver and pancreaspancreas

Endocrine systemEndocrine system

Reproductive systemReproductive system


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The Sweat TestThe Sweat Test

Measures the concentration ofMeasures the concentration ofchloridechloride andand

sodiumsodium that is excreted in sweat.that is excreted in sweat.Two reliable positive results on two separateTwo reliable positive results on two separatedays is diagnostic for CF.days is diagnostic for CF.

Clinical presentation, family history and patientClinical presentation, family history and patient

age must be considered to interpret the results.age must be considered to interpret the results.


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EpidemiologyEpidemiology

CF is aCF is a rarerare diseasediseaseApproximately 30,000 in the U.S. people have CFApproximately 30,000 in the U.S. people have CF

Over 10 million Americans are unknowing carriers.Over 10 million Americans are unknowing carriers.

Around 2,500 children with CF are born each year.Around 2,500 children with CF are born each year.

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%

CF is a disease ofCF is a disease ofCaucasiansCaucasians..


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HeritabilityHeritability

CF is aCF is a hereditaryhereditary disease.disease.

Unaffected parents can haveUnaffected parents can have

children with CF.children with CF.

Males and females are equallyMales and females are equally

likely to be diagnosed.likely to be diagnosed.


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Mapping the gene for CFMapping the gene for CF

Gene linkage studies were able toGene linkage studies were able to

map the mutation to chromosome 7.map the mutation to chromosome 7.

Classical genetics techniques wereClassical genetics techniques were

not able to accurately pinpoint thenot able to accurately pinpoint the

mutated gene.mutated gene.


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Mapping the gene for CFMapping the gene for CF

19891989: Lap: Lap--Chee Tsui, at the Hospital for Sick Children inChee Tsui, at the Hospital for Sick Children in

Toronto, clones theToronto, clones the CFTRCFTRgene. Victory tastes sweet.gene. Victory tastes sweet.

ChromosomeChromosome walkingwalking andand jumpingjumping techniques were usedtechniques were used

to identify and sequence the 180,000 bp gene.to identify and sequence the 180,000 bp gene.


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The F508 MutationThe F508 Mutation

The mutation results in the deletion of a singleThe mutation results in the deletion of a single

amino acid (Phe) at position 508.amino acid (Phe) at position 508.

A 3 base pair deletion calledA 3 base pair deletion called F508F508 is the mostis the most

common mutation causing cystic fibrosiscommon mutation causing cystic fibrosis


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Benefits of F508Benefits of F508

The F508 mutation most likely occurredThe F508 mutation most likely occurred

over50,000 years ago inover50,000 years ago in Northern EuropeNorthern Europe..

Individuals with two copies of F508 get cysticIndividuals with two copies of F508 get cystic

fibrosis and often cannot reproduce.fibrosis and often cannot reproduce.

Having one copy of F508Having one copy of F508 reduces water lossreduces water loss

duringduring choleracholera, greatly increasing the chance of, greatly increasing the chance of

survival.survival.


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The Function of CFTRThe Function of CFTR

CFTR encodes a 170 kDa, membraneCFTR encodes a 170 kDa, membrane--basedbased

protein with an activeprotein with an active transporttransport functionfunction


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From Mutation to DiseaseFrom Mutation to Disease

The mutant form of CFTRThe mutant form of CFTR

prevents chloride transport,prevents chloride transport,

causing mucus buildcausing mucus build--upup

Mucus clogs the airwaysMucus clogs the airways

and disrupts the function ofand disrupts the function of

the pancreas & intestines.the pancreas & intestines.


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CFTR MutationsCFTR Mutations

OverOver1,0001,000 mutations inmutations in

CFTR have been found.CFTR have been found.

F508 accounts for justF508 accounts for just

70%70% of CF cases.of CF cases.


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5 Classes of CFTR Mutations5 Classes of CFTR Mutations

CF Mutations can be classified by theCF Mutations can be classified by the effecteffect theythey

have on the CFTR protein.have on the CFTR protein.


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5 Classes of CFTR Mutations5 Classes of CFTR Mutations

I

Defective

Production

II

Defective

Processing

III

Defective

Regulation

IV

Defective

Conductance

V

Reduced

Amounts


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Genotype Class and MortalityGenotype Class and Mortality

Mutation class can affect diseaseMutation class can affect disease mortalitymortality..


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Genotype and PhenotypeGenotype and Phenotype

Clinical phenotypesClinical phenotypes can vary widely across mutationscan vary widely across mutations


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Newborn ScreeningNewborn Screening

Infants can easily be diagnosed with a blood testInfants can easily be diagnosed with a blood testElevated levels of trypsinogen indicate CFElevated levels of trypsinogen indicate CF

Screening programs identify 10% of cases at birthScreening programs identify 10% of cases at birth

Most hospitalsMost hospitals do not screendo not screen for CF at birth.for CF at birth.Should they?Should they?


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Genetic Carrier TestingGenetic Carrier Testing

Tests for common CF mutationsTests for common CF mutationsare available.are available.

The type of defective CF geneThe type of defective CF genecan affect the type of CFcan affect the type of CFsymptoms.symptoms.

However, genetic testingHowever, genetic testing cannotcannotfully determine how severe afully determine how severe aperson's CF will be in advance.person's CF will be in advance.


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Further ReadingFurther Reading

The Cystic Fibrosis FoundationThe Cystic Fibrosis Foundation

http://www.cff.orghttp://www.cff.org

Cystic Fibrosis on WikipediaCystic Fibrosis on Wikipedia

http://en.wikipedia.org/wiki/Cystic_fibrosishttp://en.wikipedia.org/wiki/Cystic_fibrosis

McKone et al. Effect of genotype on phenotype and mortality in cystic

fibrosis: a retrospective cohort study. Lancet2003.

The Cystic Fibrosis Mutation Database

http://www.genet.sickkids.on.ca/cftr


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Image CreditsImage Credits

http://en.wikipedia.org/wiki/Cystic_fibrosis and /wiki/CFTR_%28gene%29http://en.wikipedia.org/wiki/Cystic_fibrosis and /wiki/CFTR_%28gene%29

http://www.cff.orghttp://www.cff.org

http://adam.about.com/encyclopedia/18135.htmhttp://adam.about.com/encyclopedia/18135.htm

http://hipusa.com/eTools/webmd/Ahttp://hipusa.com/eTools/webmd/A--Z_Encyclopedia/cysticfibrosisbasics.htmZ_Encyclopedia/cysticfibrosisbasics.htm

http://prometheus.mse.uiuc.edu/research/cysticFibrosis/cysf.htmlhttp://prometheus.mse.uiuc.edu/research/cysticFibrosis/cysf.html

http://www.medicalprogress.org/news/newsarchive.cfm?news_id=237http://www.medicalprogress.org/news/newsarchive.cfm?news_id=237

http://www.musicunites.com/CF.htmhttp://www.musicunites.com/CF.htm

http://www.meddean.luc.edu/lumen/meded/elective/pulmonary/cf/cf_f.htmhttp://www.meddean.luc.edu/lumen/meded/elective/pulmonary/cf/cf_f.htm

http://learn.genetics.utah.edu/units/disorders/whataregd/cf/http://learn.genetics.utah.edu/units/disorders/whataregd/cf/http://www.sixtyfiveroses.comhttp://www.sixtyfiveroses.com

http://www.cf.ac.uk/biosi/staff/jacob/teaching/ionchan/ionchan2.htmlhttp://www.cf.ac.uk/biosi/staff/jacob/teaching/ionchan/ionchan2.html

http://www.ambrygen.com/ts/ts.htmhttp://www.ambrygen.com/ts/ts.htm

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