Cystic fibrosis (CF) inherited autosomal recessive disorder incidence of 1 in 3 000 live births carrier frequency of 1 in 25 CF affects roughly 70 000 worldwide 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 Organs Affected by Cystic Fibrosis AIRWEAYS: Clogging and infection of bronchial passages impede breathing. The infection progressively destroy the lungs. LIVER: Plugging of small bile ducts impedes digestion and discrupts liver function in perhaps 5% of patients PANCREAS: Oclusion of ducts prevents the pancreas from delivering critical digestive enzymes to the bowel in 65% of patients. Diabetes can result as well. SMALL INTESTINE: Obstruction of the gut by thick stool necessitates surgerry in about 10% of newborns REPRODUCTIVE TRACT: Absence of fine ducts, such as the vas deferans, renders 95% of males infertile. Occasionally, women are made infertile by a dense plug of mucus that blocks sperm from entering the uterus. SKIN: Malfunctioning of sweat glands causes perspiration to contain excessive salt (NaCl) • 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. CFTR gene (cystic fibrosis transmembrane conductance regulator) Location: 7q31.2 Over 1,000 mutations in CFTR have been found AF508 accounts for just 70% of CF cases Panel 1: Frequencies of CFTR mutations* CFTR Allele CFTR Allele mutation frequency (%) mutation frequency AF508 69-4% 2789+5G-M 0-3% Unknown 15-7% R1162X 0-3% G542X 2-3% G85E 0-3% G551D 2-2% R560T 0-2% AI507 1-6% R334W 0-2% W1282X 1-4% 3659AC 0-2% N1303K 1-2% A455E 01% R553X 0-9% 711+lG^T 0-1% 621+1G-+T 0-8% 1898+1G->A 0-1% R117H 0-7% 2184AA 0-1% 3849+10 kbC- VT 0-7% S549N 0-1% 1717-IG->A 0-5% 1078AT 0-03% R347P 0-3% *n=17 853. The AF508 Mutation A 3 base pair deletion called AF508 is the most common mutation causing cystic fibrosis The mutation results in the deletion of a single amino acid (Phe) at position 508. r Benefits of AF508 The AF508 mutation most likely occurred over 50,000 years ago in Northern Europe. Individuals with two copies of AF508 get cystic fibrosis and often cannot reproduce. Having one copy of AF508 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. 5 Classes of CFTR Mutations CF Mutations can be classified by the effect they have on the CFTR protein. Panel 2: Functional classification of CFTR alleles Class Functional effect of Allele mutation 1 Defective protein G542X, R553X, W1282X, production R1162X, 621-1G->T, 1717-1G->A. 1078AT, 3659AC II Defective protein AF508, AI507, N1303K, processing S549N III Defective protein G551D, R560T regulation IV Defective protein R117H. R334W, G85E, conductance R347P V Reduced amounts of 3849+lOKbC^T, functioning CFTR protein 2789+5G->A, A455E Unknown 711+lG^T, 2184DA, 1898+lG^A V_J 5 Classes of CFTR Mutations i Defective Production II Defective iii Defective IV Defective V Reduced Processing Regulation Conductance Amounts Probability of producing a child with CF: IF: Both parents have CF THEN: 100% chance child will have CF. IF: One parent has CF, the other is *not* a carrier THEN: 0% chance child will have CF (barring the very unlikely event of spontaneous mutation); 100% chance child will be a carrier. IF: One parent has CF, the other is a carrier THEN: 50% chance that child will have CF; 50% chance that child will be a carrier. IF: Both parents are carriers THEN: 25% chance that child will have CF; 50% chance that child will be a carrier; 25% chance that child will not have CF or be a carrier. Sickle Cell Anemia autosomal recessive inheritance Sickle Cell Anemia mutation in the Hemoglobin Beta Gene which can be found in the chromosome 11 abnormally shapes red blood cells. • substitution of the second nucleotide base of codon 6, adenin (A) to thymine (T) changes the codon GAG for glutamic acid to the codon GTG for valine Sickle cells Unlike normal erythrocytes, sickle cells are unable to pass through small arteries and capillaries. These become clogged and cause local oxygen deficiency in the tisues, followed by infection. Defective erythrocytes are destroyed (hemolysis). The result is chronic anemia and its numerous sequelae such as heart failure, liver damage and infection Learning deficit t Frequently ill t Infections t Oxygen deficit t Small arteries and capillaries plugged /—K)( Brain affected t Heart failure t Anemia t Hemolysis Hemophilia A X linked recessive hereditary disorder incidence about 1 in 5 000 males r Hemophilia A • 2 types of hemophilia: A and B • Hemophilia A: X linked recessive hereditary disorder • Hemophilia A results from the deficiency of blood coagulation factor VIII, which function as a cofactor in the activation of factor X to factor Xa during the intermediate phase of the coagulation cascade Genetics • Transmitted by females, suffered by males • The female carrier transmits the disorder to half their sons and the carrier state to half her dtrs • The affected male does not transmit the disease to his sons but all his dtrs are all carriers (transmission of defected X) Genetics • Factor VIII gene - Xq28, one of the largest genes -186kb, 26 exons. Its large size predisposes it to mutations In Hemophilia A there is no uniform abnormality. There are deletions, insertions, and mutations Aprox 40% of severe hemophilia A is caused by a major inversion in the gene- the breakpoint is situated within intron 22 r IV Prince Albert von Sachsen-Coburg-Gotha Alice Queen Victona D □ DOOQO Ludwig v. Hessen Heinrich von Preussen Irene Alexandra Frederick Leopold Duke of Albany a Beatrice Prince Heinrich von Battenberg Nikolaus II o Alice Iii / / § éůóóůé $ & & & i9 / # / A. X-Chromosomal inheritance of hemophilia A 100 40-55 40-130 Mental retardation, large testicles, long face Loss of coordination and certain reflexes, spine curvature, knee and ankle jerks Loss of coordination, uncontrollable movements, dementia Personality changes, uncontrollable movements, dementia Poor growth, abnormal face, slow movement Progressive muscle weakness; heart, brain, and hormone abnormalities Progressive muscle weakness; heart, brain, and hormone abnormalities Muscle weakness and wasting in adulthood Loss of coordination