ABCMdb

PMID: 16648884

Mishra A, Greaves R, Massie J
The relevance of sweat testing for the diagnosis of cystic fibrosis in the genomic era.
Clin Biochem Rev. 2005 Nov;26(4):135-53., [PubMed]

Sentences

No. Mutations Sentence Comment

94 ABCC7 p.Gly542* These mechanisms of CFTR dysfunction are intended to provide a framework for understanding the molecular basis of epithelial cell abnormalities in CF.71 Class 1: Defective Protein Synthesis Mutations in this class include the most severe CF phenotypes resulting in no protein being synthesised.2,59,67 The most common Class I mutation is G542X, which either prevents the synthesis of a stable protein or results in the production of a truncated protein due to the creation of a premature termination codon.67 The aminoglycoside antibiotics can suppress premature termination codons by permitting translation to continue to the normal termination of the transcript.72 This has shown to be promising in in vitro and in clinical trials but further studies need to be performed to make it a safer compound that may be administered to children with this class of mutation from the time of diagnosis.72 Class II: Defective Protein Processing Mutations in this class result in a CFTR protein that fails to traffic to the correct cellular localisation due to mis-folding of the protein. Login to comment 100 ABCC7 p.Pro574His Some mutations, such as P574H have a defect in folding that is less severe than ΔF508, and as a result the protein reaches the plasma membrane and retains some function.74 Figure 2. Login to comment 114 ABCC7 p.Gly551Asp ABCC7 p.Ser1255Pro In some mutations, e.g. G551D, there is minimal function and in some, e.g. S1255P, ATP is less potent at stimulating activity. Login to comment 115 ABCC7 p.Arg117His ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro CFTR is also regulated by phosphorylation of the regulatory domain but there appear to be fewer mutations in this domain than in other parts.59 Class IV: Defective Conduction Many missense mutations have been identified in the membrane spanning domains, where the CFTR gene encodes a protein that is correctly trafficked to the cell membrane and responds to stimuli but generates a reduced chloride current.59 Some examples include mutations in which arginine is replaced by histidine at residue at 117 (R117H), tryptophan at 334 (R334W), or proline at 347 (R347P). Login to comment 117 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Ala455Glu In addition, at least for R117H, the amount of time that the channel is open is also reduced.75 R117H is a particularly interesting mutation as the affected CFTR function is also determined by the M470V polymorphism and the amount of protein produced.69,76 The clinical effects vary from pancreatic insufficient CF through to no clinical disease depending on the combination of these factors.77 Class V: Reduced Abundance Mutations in this group include missense, e.g. A455E (substitution of glutamic acid for alanine) and aberrant exon splicing, e.g. 3849 10kbC→T and the intron 8 polythymidine and TG repeat sequences that regulate exon 9 splicing.67,78 These mutations produce a reduced amount of CFTR transcript and low levels of functional protein that is translocated to the cell membrane. Login to comment 121 ABCC7 p.Gln1412* ABCC7 p.Gln1412* Predicted mutations in the CFTR promoter can have similar effects by reducing the level of transcription.2,67 Class VI: Reduced Protein Stability Mutations in this novel class include protein stability mutants which cause lability of the CFTR protein, such as mutations resulting in absence of the 70-98 residues of the CFTR C-terminus.70,79 Although the C-terminus is not required for the biogenesis and chloride channel function of CFTR, it is indispensable for maintaining the stability of complex-glycosylated CFTR.2 The shortest truncation reported that causedCFwithpancreaticinsufficiencyandrecurrentpulmonary infection is Q1412X which lacks 70 amino acids. Login to comment 125 ABCC7 p.Gly551Asp ABCC7 p.Trp1282* Other mutations are often found in higher frequency in particular ethnic populations, such as the W1282X mutation in Ashkenazi Jewish populations and G551D in French Canadians.71 Such information is useful in designing mutation panels suitable for screening programs in different populations. Login to comment 131 ABCC7 p.Gly551Asp ABCC7 p.Asn1303Lys ABCC7 p.Gly542* However there is a diminishing chance of detecting a mutation after ∆F508 which has an allele frequency in CF of 70%, when one considers that the next most common mutations (in Australia) are G551D (5%), G542X (2.4%), N1303K (1.3%) andmostothermutationshaveanallelefrequencysignificantly less than 0.5%. Login to comment 157 ABCC7 p.Arg117His Warren and colleagues described a patient in whom NBS and mutation analysis suggested a diagnosis of cystic fibrosis, however the clinical course and sweat test results were not consistent with the diagnosis.68 Direct sequencing of the patient`s genomic DNA showed compound heterozygosity for ΔF508 and ΔF508C, a polymorphism not associated with clinical disease.Areport from Chmiel and colleagues presented a case where an asymptomatic female infant (3 weeks of age) was given the diagnosis of CF solely based on DNA analysis from cord blood which was positive for both the ΔF508 and R117H mutations.88 Despite any other presentations and a normal sweat chloride, she received pancreatic enzyme supplements. Login to comment 244 ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Gly551Ser ABCC7 p.Ser1455* ABCC7 p.Asp1152His Highsmith and colleagues (1994) studied 23 patients with pulmonary disease characteristic of CF but with a normal sweat test and identified a point mutation in intron 19 of the CFTR gene, termed 3849+10kb C-T.15 This mutation produces an alternative splicing site and decreased amounts of CFTR mRNA can be detected.16 Thus, according to the classification of the CFTR mutations, this mutation falls into Class V.16,67 Other mutations associated with normal or borderline sweat electrolytes are R117H, D1152H, A455E, G551S and 2789+5G - A.9,24,78 An interesting phenotype, presenting with elevated sweat chloride concentration in the absence of other CF symptoms, has been described in a patient with a nonsense mutation, S1455X.105 This mutation truncates 26 amino acids from the C-terminus of the protein product. Login to comment 246 ABCC7 p.Ser1455* CFTR mRNA transcripts bearing the S1455X mutation were normally processed and functional, which therefore suggests that the truncated stretch C-terminal amino acid plays some role in the sweat gland only. Login to comment 367 ABCC7 p.Arg117His Genetic counselling after carrier detection by newborn screening when one parent carries DeltaF508 and the other R117H. Login to comment 440 ABCC7 p.Pro574His Processing of CFTR bearing the P574H mutation differs from wild-type and deltaF508-CFTR. Login to comment 446 ABCC7 p.Arg117His ABCC7 p.Arg117Cys Nat Genet 1993;5:274-8. 77. Massie RJ, Poplawski N, Wilcken B, Goldblatt J, Byrnes C, Robertson C. Intron-8 polythymidine sequence in Australasian individuals with CF mutations R117H and R117C. Login to comment