ABCMdb

PMID: 9674722

Schwiebert EM, Benos DJ, Fuller CM
Cystic fibrosis: a multiple exocrinopathy caused by dysfunctions in a multifunctional transport protein.
Am J Med. 1998 Jun;104(6):576-90., [PubMed]

Sentences

No. Mutations Sentence Comment

174 ABCC7 p.Gly551Asp Secondly, it has been shown that a segment of CFTR that included the first nucleotide-binding domain (NBD1) and the regulatory, or R, domain of CFTR interacted physically with ENaCs and that the severe disease-associated mutation in NBD1, G551D, prevented negative modulation of ENaCs by CFTR (74). Login to comment 218 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Trp1282* ABCC7 p.Gly542* The number of missense or point mutations (frequent examples are R117H and G551D), nonsense (frequent examples are G542X and W1282X), and frameshift mutations within CFTR has reached more than 700, according to the CF Genetic Analysis Consortium. Login to comment 223 ABCC7 p.Gly551Asp ABCC7 p.Pro574His ABCC7 p.Ala455Glu ABCC7 p.Arg553* ABCC7 p.Gly551Ser ABCC7 p.Gly542* ABCC7 p.Gln493* ABCC7 p.Ser549Asn ABCC7 p.Arg553Gln ABCC7 p.Phe508Cys ABCC7 p.Ala559Thr They include another deletion mutation at amino acid position 507 (⌬I507), several missense mutations (F508C, G551D, G551S, A455E, R553Q, P574H, S549N, A559T), and some nonsense mutations (G542X, R553X, Q493X). Login to comment 224 ABCC7 p.Trp1282* ABCC7 p.Gly1244Glu ABCC7 p.Gly1349Asp ABCC7 p.Ser1255Pro ABCC7 p.Trp1316* ABCC7 p.Ser1255* ABCC7 p.Asp1370Asn ABCC7 p.Lys1250Met ABCC7 p.Lys1250Gln In NBD2, a few key mutations have been found that include missense mutations (G1349D, D1370N, K1250M, K1250Q, G1244E, S1255P) and several nonsense mutations (W1282X, S1255X, W1316X). Login to comment 226 ABCC7 p.Gly551Asp ABCC7 p.Gly1349Asp In particular, ⌬F508, G551D, and G1349D have been well studied as severe CF disease-causing mutations. Login to comment 228 ABCC7 p.Gly551Asp Many of these mutations, especially G551D, occur at residues completely conserved among CFTR, MDR, and the other members of the ATP-binding cassette transporter family that lies in the heart of a Walker A binding motif for ATP in this ATP-binding domain. Login to comment 229 ABCC7 p.Gly551Asp ABCC7 p.Gly1349Asp An analogous mutation to G551D, G1349D, also occurs in CF patients but in the second NBD. Login to comment 231 ABCC7 p.Gly551Asp As such, G551D affects severely CFTR Cl- channel function (26,88-90). Login to comment 232 ABCC7 p.Gly551Asp Moreover, G551D prevents CFTR from interacting with ORCCs (26,88) and ENaCs (74). Login to comment 233 ABCC7 p.Gly551Asp These results may explain why the G551D genotype causes a more severe disease phenotype (84,85). Login to comment 234 ABCC7 p.Gly551Asp However, the explanation may not be that simple, because two studies have found CF patients with milder disease who carry the G551D mutation (91,92). Login to comment 237 ABCC7 p.Gly551Asp ABCC7 p.Gly1349Asp Creation of transgenic mice carrying some of the more well-known mutations such as ⌬F508, G551D (93), and G1349D as well as others described below may sort out these issues. Login to comment 238 ABCC7 p.Pro574His ABCC7 p.Ala455Glu ABCC7 p.Gly551Ser Some of these mutations, however, such as A455E, P574H and G551S have been associated either with less severe pulmonary disease and/or less compromised Cl- channel function. Login to comment 239 ABCC7 p.Ala455Glu A455E causes only a subtle decrease in CFTR Cl- channel activity and fails to prevent regulatory interaction with ORCCs (88). Login to comment 242 ABCC7 p.Arg117His Of interest, one of these mutations near predicted membrane-spanning ␣-helix 1 of TMD1 of CFTR, R117H, correlates with high incidence to a second disorder, congenital bilateral absence of the vas deferens (CBAVD), which causes infertility in males (94-96). Login to comment 243 ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Gly314Glu ABCC7 p.Arg347Glu Other mutations in TMD1 which affect function and cause disease include other arginines in predicted ␣-helix 6, R334W, R347P, and R347E (97,98) and a glycine, G314E, in ␣-helix 5 (99). Login to comment 246 ABCC7 p.Arg1070Gln ABCC7 p.Arg1066Cys ABCC7 p.Arg1066Leu ABCC7 p.Arg1066His ABCC7 p.Arg1030Glu Mutations in TMD2 cluster in ␣-helix a loop between predicted ␣-helices 10 and 11 and include R1030E, R1066H, R1066C, R1066L, and R1070Q (100). Login to comment 248 ABCC7 p.Gly551Asp All mutations studied in relation to lung disease phenotype cause a range of disease that is significant but not as severe as patients that carry G551D or ⌬F508. Login to comment 299 ABCC7 p.Trp1282* ABCC7 p.Gly542* ABCC7 p.Ser1455* Examples of such nonsense mutations are G542X in NBF1, W1282X in NBF2, and S1455X in the C-terminus of the CFTR protein. Login to comment