intro_s12 - Cystic fibrosis Cystic fibrosis is a hereditary...

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Cystic fibrosis Cystic fibrosis is a hereditary disease that causes certain glands to produce abnormal secretions, resulting in tissue and organ damage, especially in the lungs and the digestive tract. It is the most common inherited disease leading to a shortened life span among white people in the United States. It occurs in about 1 of 3,300 white infants and in 1 of 15,300 black infants. It is rare in Asians. It is equally common in boys and girls. Cystic fibrosis results when a person inherits two defective copies of the CFTR ( Cystic Fibrosis Transmembrane Conductance Regulator )-encoding gene. CFTR is a member of the ABC Transporter Family (for ATP Binding Cassette Transporters; called this because they all bind and hydrolyze ATP). CFTR appear to function mainly as chloride ion channel and/or regulator of other ion channels, thereby regulating the transport of chloride and sodium (indirectly, through its effect on ENaC, epithelium sodium channel) across cell membranes. As shown in the above figure, CFTR has 5 predicted domains: 2 transmembrane domains with 6 transmembrane helices each, 2 NBDs (nucleotide binding domains), and one R domain. NBDs serve multiple roles including opening and closing the CFTR channel as well as perhaps binding and regulating proteins in the cell by altering the gating of other ion channels. The R-domain has more than one function. In addition to it's inhibitory role in channel gating (when unphosphorylated) the R- domain seems to enable the NBDs to bind and hydrolyze ATP more efficiently (when the R- domain is phosphorylated). It also appears to use its C-terminus and N-terminus for targeting and regulation, respectively. There is increasing evidence that CFTR is able to use its intracellular loops to help in gating, providing a mainly stimulatory effect in pore opening overall. Consequences of the molecular variants in CF range from mutations leading to premature termination of mRNA translation, and thus essentially no protein production (class 1), to those leading to marginally reduced activity (classes 4 and 5). In class 2 mutations, which include the most common CF mutation, Phe- 508, the CFTR protein fails to mature properly in the biosynthetic pathway, with degradation of translated protein before it can progress past the endoplasmic reticulum. Therefore, in people with cystic fibrosis,
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This note was uploaded on 11/11/2011 for the course BIO 7.344 taught by Professor Bobsauer during the Spring '08 term at MIT.

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intro_s12 - Cystic fibrosis Cystic fibrosis is a hereditary...

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