Cellular Membrane Disorders- ER & Golgi

- AR - cystic fibrosis transmembrane conductance regulator (CFTR) mutation (Cl ion channel in PM) - Predominant Class II mutations (incorrect protein folding) (remember, class 1 means nothing is produced from mRNA) - Would fxn normally if prot was transported to PM Protein is ejected from ER back to cytosol and degraded
This disease is caused not because the mutation inactivates the protein, but b/c the active protein is discarded b4 it reaches the plasma membrane

After many infections of chronic respiratory infections - Chronic cough - Dyspnea-shortness of breath - Irreversible bronchial dilation and thickened bronchial walls - Dilated central bronchi - Hyperexpansion - Mucoid impaction à obstruction and 2y infection à fibrosis à bronchiectasisRespiratory failure: most common cause of death

- Defective routing 1- CF: CFTR 2- Hypercholiesterolemia: LDL receptor --cont’d-- - Defective protein folding/conformational errors 1- Alzheimer’s-extracell. aggregation of Beta amyloid & intraneuronal aggregation of tau 2- Parkinson’s 3- Huntington’s- expansion of CAG repeat in huntington sequence: aggregation of abnormal protein in nucleus 4- Creuzfeld Jacob disease Cataracts

§Abnormal protein folding → aggregation •Prion protein (PrP): GPI-linked α-helix protein on outer membrane surface of neuron membrane §Abnormal folding: β-sheet filaments (protease resistant) §“infectious”: converts normal PrP to abnormal aggregating form §Scrapie (sheep) / BSE (cattle) / vCJD (human)The other 3 are: Alzheimers, Parkinsons, Huntington's

- Mutations in LDL receptor à inc plasma cholesterol, incr synthesis of LDL - 1/500 hets, 2-3x plasma cholesterol (homozygotes 6x) - Class II: defective transport from rER to Golgi (don’t reach PM) Major risk factor for Coronary heart disease (CHD), premature atherosclerosis

Mucolipidosis is the accumulation of glycoproteins and glycolipids
- Deficiency of N-acetylglucosamine phosphotransferase à absence of M6P tag in the cis golgi
- Acid hydrolases lacking M6P are secreted extracellularly à undigested material accumulates as inclusion bodies and progressively damage cells.
- Skeletal abnormalities, coarse features, restricted joint movement, psychomotor retardation
- Enlarged liver, spleen, heart valves; death: CHF/RTI Life expectancy < 10 yrs