ABCMdb

PMID: 19760540

Lommatzsch ST, Aris R
Genetics of cystic fibrosis.
Semin Respir Crit Care Med. 2009 Oct;30(5):531-8. Epub 2009 Sep 16., [PubMed]

Sentences

No. Mutations Sentence Comment

63 ABCC7 p.Trp1282* ABCC7 p.Gly542* The most common muta- Table 1 Most Common Genotype Based on Ethnicity Ethnicity Genotype Chromosome Frequency (%) Caucasian (N. European) ~F508 70-80 Caucasian (S. European) ~F508 50-55 African Americans ~F508 48 3120 þ 1 G-to-A 12 Ashkenazi Jews W1282X 48 ~F508 30 Hispanic (U.S.) ~F508 46 G542X 5.4 Adapted from Knowles et al.13 534 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 30, tion in this group is ~F508, which results in >99% of the protein being degraded as opposed to $75% in the normal individual.8 This mutation causes a three-base pair deletion in exon 10 specifically affecting the integral tertiary interaction between the N-terminus of NBD-1 and C-terminus of transmembrane segment-4 regulating CFTR channel gating.5,6,25 Interestingly, the ~F508 CFTR has been found to be a ''temperature sensitive`` mutant given that, in vitro, it can be delivered by gene therapy vectors to the apical membrane if cells are incubated at 23 to 308C.9,13 Class III and IV mutations typically confer more mild disease. Login to comment 65 ABCC7 p.Arg117His ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro Class III mutations cause defective protein regulation due to alterations of NBD1 and NBD2 that prevent channel activation by cyclic adenosine monophosphate (cAMP) or adenosine triphosphate (ATP).6-8 Additionally, some mutations within this class alter the function of ion channels regulated by CFTR such as the outwardly rectifying chloride chan- nel26 and the ROMK2 potassium channel.27 Class IV mutations, such as R347P, R117H, and R334W, yield conduction abnormalities resulting in diminished chloride conductance. Login to comment 96 ABCC7 p.Arg117His ABCC7 p.Asn1303Lys More thorough DNA analysis now demonstrates that CF mutation carriers with chronic idiopathic pancreatitis (CIP) are likely to be compound heterozygotes with a severe and mild mutation or homozygous for commonly causing CF mutations.36,37 Cohn et al, for example, demonstrated an association between chronic pancreatitis and several CFTR mutations: ~F508, N1303K, and R117H. Login to comment 99 ABCC7 p.Arg117His ABCC7 p.Arg553* ABCC7 p.Gln493* ABCC7 p.Arg560Thr They also found an association with ~F508 and R117H in addition to Q493X, R560T, R553X, and 621 þ 1(G!T).34 Noone et al found an association between chronic pancreatitis and the 5T allele associated with complex alleles or in CFTR compound heterozygotes, but no significantly increased frequency has been found with the 5T allele alone.36,39 Finally, there appears to be an additive effect with being a CFTR compound heterozygote and the presence of N34S mutations of the pancreatic secretory trypsin inhibitor (PSTI).36,39 These studies demonstrate the increased risk of chronic pancreatitis due to an abnormally functioning CFTR protein (but may be due to just one mutant CFTR allele37 ). Login to comment 105 ABCC7 p.Arg117His DNA analysis in $40 to 85% of patients reveals an autosomal recessive pattern including either a severe and mild CF mutation or two mild mutations.13,41,42 Most patients are compound heterozygotes, and ~F508 is present on one allele in $40% of this group.42,43 Other common mutations include R117H (3 536 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 30, to 14%) and the 5T variant of the polythymidine tract of the intron 8 (IVS8) acceptor splice site. Login to comment