rER & Golgi

Question 1

cystic fibrosis

Answer 1

Defect: Protein folding defect ! defective transport from rER to Golgi; mutation in CFTR (Cl- ion channel) – single AA deletion of F508
Mode of Inheritance: Autosomal recessive
Mechanism: CFTR is misfolded in the ER so it keeps getting ejected back to
cytosol and degraded in proteasomes
Characteristics: young white kid; normal at birth, failure to thrive, recurrent
pneumonia, sputum +pseudomonas; PE: scattered rales/crackles throughout
lungs, rhonchi; diagnostic: axillary sweat test; bronchiectasis; respiratory
failure is most common cause of death (clubbing is often seen due to respiratory insufficiency but this is not characteristic of just CF – seen in other diseases as well)
Key Words: CFTR mutation, fibrosis in lungs, sweat, autosomal recessive, respiratory failure

Question 2

Familial Hypercholesterolemia

Answer 2

Defect: Protein folding defect ! defective transport from rER to Golgi; mutation of LDL-R (cell surface receptor for LDL; transmembrane protein) – CLASS II
Mode of Inheritance: Genetically related
Mechanism: Mutation inhibits proper folding of LDL-R!ejected from ER, polyubiquinated, degraded by proteasome
Characteristics: increased plasma cholesterol levels; increased LDL synthesis; major risk factor for CHD, premature atherosclerosis, Xanthomata, corneal arcus, Xanthelasmata
Key Words: LDL-R, CHD (CAD), plasma cholesterol, Xanthomata, Xanthelasmata

Question 3

I-cell disease (mucolipidosis II)

Answer 3

Defect: Transport defect – absence M6P protein tag (N-acetylglucosamine phosphotransferase deficiency in cis-golgi) – also considered a LYSOSOMAL STORAGE DISEASE
Mode of Inheritance: Autosomal recessive
Mechanism: The absence of M6P tag results in lysosomal enzymes (aka acid hydrolases) being sent to PM and secreted extracellularly (default pathway), rather than being sent to lysosomes. Degradation of cellular inclusions within the lysosome does not take place because the lysosomes are devoid of lysosomal enzymes!accumulation of
inclusions. [*Note: the defect is NOT in the lysosomal enzymes, but rather in
the Golgi-resident modification enzyme mentioned above.]
Characteristics: progressive disease; high levels of acid hydrolases in the
blood; skeletal abnormalities, coarse facial features, restricted joint movement, psychomotor retardation, enlarged spleen, liver, & heart valves, death due to
CHF or RTI, life expectancy ~10 years
Key Words: absence of M6P, waste products in inclusion bodies, coarse facial features, enlarged liver/spleen, death CHF