MadSci Network: Medicine

Re: what types of diseases are assoc'd with damaged cell membrane transporters?

Date: Fri Jan 4 09:34:58 2002
Posted By: Michael Maguire, Faculty,Case Western Reserve Univ.
Area of science: Medicine
ID: 1008195470.Me

There are many, many diseases associated with missing, mutant or 
misregulated membrane transport systems.  

Probably the best known is CFTR (cystic fibrosis transmembrane 
regulator).  This is a chloride ion channel of most epithelial cells in 
the body.  About half of CF patients have an identical mutation that 
prevents the protein from folding properly during its synthesis.  Because 
it is misfolded, the cell recognizes the "damaged" protein and degrades 
it.  It therefore never reaches the cell membrane.  Without this chloride 
channel, epithelial cells cannot properly regulate chloride transport 
which secondarily causes severe problems with sodium and water 
transport/secretion.  In the lung, this leads to very thick mucus in the 
alveolae that cannot be cleared, thus plugging the lungs and providing a 
very nice growth environment for bacteria, particularly Pseudomonas 
aeruginosa and Burkholderia cepacia.  CF patients eventually die from 
suffocation, brought on by recurring bacterial infections that damage the 
lungs irreversibly over time.

Virtually every cell membrane transport system known, when mutated, can 
cause disease, some very severe, some not so severe.  As a prime example, 
has been elegantly worked out in the kidney by Rick Lifton and colleagues 
at Yale University.  Dr. Lifton has discovered mutations in several 
different types of transporters all along the kidney nephron.  The disease 
and its consequences depend not only on the particular transporter 
involved, but where along the length of the nephron that particular 
transporter is expressed.  A good place to start would be a recent review 
by Lifton,R.P., Gharavi,A.G., and Geller,D.S. "Molecular mechanisms of 
human hypertension", Cell 104:545-556(2001).

I would note also that it doesn't have to be a mutation in a transporter.  
Many examples are known where mutations in a membrane hormone receptor 
causes a problem.

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