Cystic Fibrosis TEST ONLY PDF

Cystic Fibrosis • Autosomal recessive (Mucovicidosis) • CFTR gene mutation o Codes for chloride ion transport channel to effect fluid secretion, epithelial lining of resp, GI, repro tracts o Mutation has thick secretions causing: § Obstruction and chronic recurrent lung infection § Pancreatic insuff...

Cystic Fibrosis • Autosomal recessive (Mucovicidosis) • CFTR gene mutation o Codes for chloride ion transport channel to effect fluid secretion, epithelial lining of resp, GI, repro tracts o Mutation has thick secretions causing: § Obstruction and chronic recurrent lung infection § Pancreatic insufficiency § Hepatic cirrhosis § Intestinal obstruction Inheritance of Cystic Fibrosis (Autosomal recessive) • Heterozygotes usually show no symptoms, but may have higher incidence of respiratory and pancreatic diseases • Most common mutation is ΔF508 or Phe508del CFTR Gene • Cystic fibrosis transmembrane conductance regulator on chromosome location 7q31.2 • Most pathogenic mutation: F508del (80% of cases) CFTR Protein • Consists of: o 2 transmembrane domains (form the chloride channel) o 2 intracellular nucleotide (ATP) binding domains o 1 intracellular regulatory domain • Normal Function: Results in opening of chloride ion channel CFTR Functions • Primary Function: Chloride Conductance Channel o Function of normal CFTR is tissue-specific o Role in sweat glands is different from that in Respiratory and GI epithelium • Secondary Function: CFTR controls other Ion channels and cell processes o Inhibits sodium uptake in epithelial sodium channels (ENaC)except in sweatducts o Regulates transport of bicarbonate ions o Regulates cellular processes involved in ATP transport and mucus secretion • CFTR mutations result in: o Reduced chloride secretion into lumen o increase in sodium uptake into the cell from the lumen (increased ENaC activity) o Transport of water into cells leads to dehydration of mucus in lumen o Genetic modifier: Pulmonary manifestations may be modified by polymorphisms on several genes § Mannose-binding lectin 2 (MBL 2) § Transforming growth factor beta 1 (TGF B1) § Interferon related developmental regulator 1 (IFR D1) o Environmental modifiers: smoking CFTR in Sweat Ducts: • Normal CFTR function facilitates reabsorption of chloride and sodium ions • In CF, loss of CFTR function leads to o Decreased sodium and chloride reabsorption o Production of hypertonic sweat → salt depletion and heat stroke, especially in infants CFTR in Respiratory and Intestinal Cells • Normal function of CFTR in respiratory and intestinal cells: o Active secretion of chloride into the lumen o Decreases sodium uptake from luminal fluid into the cell Classification of CFTR Mutations: • 7 overlapping groups based on their functional impairment of CFTR channel • CFTR gene mutations can be classified in up to 7 overlapping groups, based on their functional impairment of the o Class I mutation: § near absence of the CFTR protein § mainly stop codon mutations and frameshift mutations leading to a premature termination codon o Class II III IV V VI VII Classification oversimplifies pathologic mutations F508del mutation predominantly Class II, has characteristics of Class II and VI Tissue/Organ Changes in CF • Dysfunctional or absent CFTR function results in dehydrated, thickened mucus secretions o Lung: § mucopurulent secretions § impaired mucociliary clearance § chronic infection, inflammation → progressive structural lung damage o Pancreas o GI Tract: defective bicarbonate secretion → intestinal mucus obstruction and meconium ileus o Liver: Hyperviscous biliary secretions, cholestasis → cirrhosis Pulmonary Changes in CF • Viscous mucus secretions and defective mucociliary action leads to secondary obstruction and infection o Bronchiectasis: permanent dilation o Recurrent and persistent infections o Abscess formation