Phenylalanine deletion

Approximately 90% of CF patients carry a loss-of-function CFTR mutation on at least one allele that results in deletion of phenylalanine 508 (F508del) in the first CFTR nucleotide-binding domain [7]. The F508del prevents the proper domain folding and assembly of the multidomain CFTR protein during its biogenesis in the endoplasmic... 

Some 70 per cent of all cystic fibrosis patients exhibit a specific three-base-pair deletion in the gene, which results in the loss of a single amino acid (phenylalanine 508) from its final polypeptide product. Other cystic fibrosis patients display various other mutations in the same gene. 

Deletion of the phosphate ester oxygen of 1 results in 4-phosphono-phenylalanine, Phe(P03H2) 8 (Scheme 1) which was incorporated in Abl and Src... 

The majority of cases of cystic fibrosis result from deletion of phenylalanine at position 508 (AF508), which interferes with proper protein folding and the posttranslational processing of oligosaccharide side chains. The abnormal chloride channel protein (CFTR) is degraded by the cytosolic proteasome complex rather than being translocated to the cell membrane. Other functional defects in CFTR protein that teaches the cell membrane may also contribute to the pathogenesis of cystic fibrosis. 

Approximately 70% of CFTR mutants worldwide are due to deletion of a single phenylalanine (AFS08) that interferes with CFTR folding this mutant CFTR is recognized as abnormal and is degraded (broken down). 

Mutations in the phenylalanine hydroxylase gene occur in all thirteen exons of the gene. The majority are missense mutations, although splice, nonsense, and silent mutations, as well as deletions and insertions, have been found. 

A number of residues may be replaced with other amino acids without apparent change in enzymic activity. These replacements include nor-leucine for methionine at positions 26 and 32 87), phenylalanine for tyrosine 27 92), and glycine for histidine 46 85). As mentioned above, deletion of histidine 8 is without deleterious effect. The two remaining residues of histidine at positions 121 and 124 may also be ruled out as components of the active site since the former is, stereoehemically, far on the other side of the molecule and the latter is replaced by leucine in nuclease from the Foggi strain of Staphylococcus aureus. 

For instance, MALDI analysis allows the detection of a mutation often present in patients with cystic fibrosis (see Figure 8.32). [175] This mutation corresponds to the deletion of three base pairs, which leads to the loss of a phenylalanine residue in the protein. Using appropriate primers for the PCR reaction, the normal gene presents a 59-base fragment whereas the mutated one presents a 56-base fragment. 

Fig. 1. Comparison of amino acid sequences of apolipoprotein from 10 species. Sequences are aligned against human apoE4. Hu, Human (Rail et ai, 1982a) Ba, baboon (Hixson et

---