CYSTIC FIBROSIS : CYSTIC FIBROSIS Mrs. Rani Ashok
Assistant Professor in Zoology
Lady Doak College, Madurai - 2 Slide 2: "Woe is the child who tastes salty from a kiss on the brow, for he is cursed, and soon must die.” -Northern European Folklore Slide 3: Cystic Fibrosis (CF) is a lethal inherited disease that affects the lungs, digestive system, sweat glands, and male fertility
Its name derives from the fibrous scar tissue which develops in the pancreas Figure 8 CYSTIC FIBROSIS Slide 4: Cystic Fibrosis affects the body’s ability to move salt and water in and out of a cell
This results in the lungs and the pancreas secreting a thick mucus
This mucus blocks passageways and prevents proper function CYSTIC FIBROSIS Notable History : Notable History 1905
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 : 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 : Clinical Aspects Cystic fibrosis affects the entire body Lungs and sinuses
GI, liver and pancreas
Reproductive system Epidemiology : 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. Heritability : Heritability CF is a hereditary disease.
Unaffected parents can have children with CF.
Males and females are equally likely to be diagnosed. Slide 10: Eggs Sperm Baby with CF Normal carrier Normal carrier Normal non-carrier Carrier Mom Carrier Dad Signs and Symptoms : Signs and Symptoms Thick, viscous mucus secretion in the lungs
Changes in color and amount of sputum
salty skin or poor growth
Weight loss (abdominal swelling) Molecular and Genetic Basis of Cystic Fibrosis : Molecular and Genetic Basis of Cystic Fibrosis Mapping the gene for CF : 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. Gene Locus : Gene Locus Chromosome 7; Locus 7q31.2 The CFTR gene:
is 250, 000 bp long
contains 27 exons
the protein has 1, 480 amino acids with a molecular mass of 168, 138 Da
nucleotide of ~ 6,500 Mapping the gene for CF : 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 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 : 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 : The Function of CFTR CFTR encodes a 170 kDa, membrane-based
protein with an active transport function Slide 19: The CFTR protein plays a vital role in mucus function
The CFTR protein helps to keep mucus from becoming thick Role of CFTR Protein Role of CFTR Protein : Role of CFTR Protein In CF, the CFTR cannot allow chloride ions to move out of the mucus-producing cells
This means water doesn’t leave and it results in the mucus becoming thick
This in turn blocks the passageways, and allow bacteria to feed off the mucus, which results in more infections From Mutation to Disease : 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 : CFTR Mutations Over 1,000 mutations in
CFTR have been found.
ΔF508 accounts for just
70% of CF cases. The Sweat Test : 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. 5 Classes of CFTR Mutations : 5 Classes of CFTR Mutations CF Mutations can be classified by the effect they
have on the CFTR protein. 5 Classes of CFTR Mutations : 5 Classes of CFTR Mutations I
Amounts Genotype Class and Mortality : Genotype Class and Mortality Mutation class can affect disease mortality. Genotype and Phenotype : Genotype and Phenotype Clinical phenotypes can vary widely across mutations Newborn Screening : 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 : 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. Carrier Screening : Carrier Screening Population-based screening:
Particular genetic carrier tests offered to everyone in the general population
Targeted population-based screening:
Carrier screening limited to particular groups of people determined to be at higher risk for specific genetic disorders
e.g. Ethnicity-based carrier screening Carrier Testing : Carrier Testing To determine an individual’s carrier status for a specific genetic disease
Not usually offered on a population basis Carrier Testing : Carrier Testing Available to clients with a family history of an autosomal recessive or X-linked genetic condition for which carrier testing available
e.g. Fragile X syndrome, Duchenne muscular dystrophy, Hemophilia A or B
e.g. PKU, Alpha-1-antitrypsin deficiency, Galactosemia Ethnicity-Based Genetic Carrier Screening : Ethnicity-Based Genetic Carrier Screening Purpose: To detect couples at risk for prenatally diagnosable genetic diseases
Types of tests offered based on clients’ ethnic background
Offered to all individuals of that ethnic background (targeted population screening) Slide 34: Population Condition Carrier Frequency CARRIER FREQUENCIES BASED ON ETHNIC ORIGIN CF Carrier Results : CF Carrier Results Many tests detect a majority but not all carriers
Detection rates differ by ethnicity
Negative results do not eliminate risk
Different mutations may confer different risks
Example: CFTR R117H mutation and 5T allele
Genetic consultation is available to carriers and strongly advised for carrier/carrier couples Carrier Rates: Cystic Fibrosis : Carrier Rates: Cystic Fibrosis Drug Therapies : Drug Therapies Medication are often aerosolize and can be inhaled
Antibiotics to fight lung infections
Enzyme supplements Slide 38: How can Gene Therapy be used to treat patients who suffer from Cystic Fibrosis (CF)? Gene Therapy : Gene Therapy SmaRT-discovered by Xiaoming Li
Interferes with the processing of RNA
Synthesis of DNA probe to locate the gene
make copies of normal and abnormal gene
Problems with gene therapy
“Fooling with Mother Nature” Slide 40: Gene therapy is currently the most ambitious approach to curing Cystic Fibrosis
Nondefective copies of the CFTR gene are introduced into affected cells, where they are taken up and used to create the CFTR protein
This will result in the mucus functioning properly and a stop to Cystic Fibrosis Gene Therapy Slide 41: It has been attempted to deliver the normal CFTR gene to the bronchial epithelium by aerosol spray, using a viral vector (usually an adenovirus)
This viral vector would contain the genetic material for the CFTR gene
The vector would be able to enter a cell inside the body and insert the genetic material for the CFTR gene into the cells DNA Gene Therapy Slide 42: This would result in the cell having a normal CFTR gene and an end to CF
Thus far the attempts have not been completely successful, as most patients develop an immune response against the virus during the course of therapy Gene Therapy Slide 43: Thank You