ABCMdb

PMID: 16132229

Eudes R, Lehn P, Ferec C, Mornon JP, Callebaut I
Nucleotide binding domains of human CFTR: a structural classification of critical residues and disease-causing mutations.
Cell Mol Life Sci. 2005 Sep;62(18):2112-23., [PubMed]

Sentences

No. Mutations Sentence Comment

51 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp Most of the class III mutants (affecting Cl-channel gating) are located within the ATP-binding sites, as exemplified here by G551D (salmon). Login to comment 108 ABCC7 p.Val520Phe ABCC7 p.Val456Phe Examples are V456F [33] and V520F [34] (labeled C and K, respectively, in fig. 2) which involve residues buried in the interior of the NBD1 subdomain. Login to comment 130 ABCC7 p.Asn1303Lys Several class II mutations (defective CFTR folding and trafficking), such as the relatively frequent N1303K mutation (labeled J in fig. 2), involve buried residues (fig. 1). Login to comment 131 ABCC7 p.Pro574His ABCC7 p.Ala559Thr Other examples (fig. 1) are: (i)A455E [38-40] (labeled B in fig. 2); (ii) P574H [40, 41] (labeled S in fig. 2); (iii) A559T [42, 43] (labeled Q in fig. 2). Login to comment 132 ABCC7 p.Pro574His ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu Worth noting is that A455E and P574H are mild alleles, as they have been found associated with preserved pancreatic function and residual secretion of chloride; in addition, a correlation between the A455E mutation and mild pulmonary disease has also been reported [38]. Login to comment 134 ABCC7 p.Val456Phe Accordingly, the missense mutation V456F (labeled C in fig. 2), which involves a topohydrophobic position buried in NBD1 (see above), was also reported in a patient suffering from a mild (pancreas-sufficient) form of CF [33]. Login to comment 136 ABCC7 p.Asn1303Lys However, the N1303K mutation (labeled J in fig. 2), which involves a position buried in NBD2, was classified not as a mild, but as a severe mutation [44]. Login to comment 144 ABCC7 p.Gly480Cys Another class II mutation, G480C, involves a non-buried position (labeled E in fig. 2). Login to comment 145 ABCC7 p.Gly480Cys Similarly to ∆F508, the G480C mutant has been found to be defective in its intracellular processing and to exhibit chloride channel properties when allowed to traffic in Xenopus oocytes [46]. Login to comment 147 ABCC7 p.Gly480Cys We should also stress here that both ∆F508 and G480C, which are class II mutations affecting residues possibly involved in domain-domain interactions, are considered as clinically severe mutations. Login to comment 148 ABCC7 p.Gly480Cys Accordingly, mouse models carrying the severe ∆F508 and G480C mutations have been generated to provide valuable in vivo systems to test novel therapeutic approaches [47]. Login to comment 161 ABCC7 p.Gly551Asp The most striking example is the G551D missense mutation (labeled N in fig. 2) which involves a residue located in the LSGGQ motif of the NBD1 ABC signature of the conventional ATP-binding site B (fig. 1). Login to comment 163 ABCC7 p.Gly551Asp Interestingly, in CF patients, the defective function of the appropriately localized G551D protein could be rescued by genistein [49]. Login to comment 165 ABCC7 p.Ser549Arg However, S549R (labeled M in fig. 2), which also involves a residue of the NBD1 ABC signature participating in the binding of the ATP γ-phosphate in the conventional site B, was identified as a class II mutation (fig. 1). Login to comment 177 ABCC7 p.Gly550Glu Thus, like the G550E mutation affecting the NBD1 ABC signature [54], a R555 mutation may restore (to some extent) the interactions disrupted by the ∆F508 mutation. Login to comment 182 ABCC7 p.Asp579Gly The D579G mutation has been observed in patients with pancreatic sufficiency and a mild pulmonary phenotype [55, 56]. Login to comment 185 ABCC7 p.Thr582Arg The T582R mutation is severe, with lung and pancreatic involvement [57]. Login to comment 189 ABCC7 p.Tyr577Phe The Y577F mutation has been shown to be associated with severe lung disease and elevated sweat chloride levels (http: //www.genet.sickkids.on.ca/cftr). Login to comment 227 ABCC7 p.Tyr563Asn ABCC7 p.Tyr563Asn ABCC7 p.Tyr563Asp ABCC7 p.Tyr563Cys Missense mutations affecting Y563 (Y563N, Y563D, Y563C) have been reported, reduced levels of mature CFTR being observed for Y563N [40]. Login to comment 247 ABCC7 p.His620Gln ABCC7 p.His484Arg ABCC7 p.Tyr1307Cys ABCC7 p.His620Pro ABCC7 p.Tyr515His (B) Ribbon representation of the NBD aa1 - aa2 segment of the three experimental MalK structures and of mCFTR NBD1, with the CFTR F508 and MalK F98 being shown in atomic details involves the exposed F508 residue, only a few missense mutations affecting these exposed aromatic residues have been reported: H484R, Y515H, H620P, H620Q and Y1307C (http://www.genet.sickkids.on.ca/cftr). Login to comment 330 ABCC7 p.Val1397Glu Hum. Genet. 93: 67-73 34 Jones C. T., McIntosh I., Keston M., Ferguson A. and Brock D. J. (1992) Three novel mutations in the cystic fibrosis gene detected by chemical cleavage: analysis of variant splicing and a nonsense mutation. Hum. Mol. Genet. 1: 11-17 35 Petreska L., Koceva S., Gordova-Muratovska A., Nestorov R. and Efremov G. D. (1994) Identification of two new mutations (711 +3A→G and V1397E) in CF chromosomes of Albanian and Macedonian origin. Login to comment 336 ABCC7 p.Pro574His ABCC7 p.Ala455Glu 333: 95-99 39 De Braekeleer M., Allard C., Leblanc J. P., Simard F. and Aubin G. (1997) Genotype-phenotype correlation in cystic fibrosis patients compound heterozygous for the A455E mutation. Hum. Genet. 101: 208-211 40 Van Oene M., Lukacs G. L. and Rommens J. M. (2000) Cystic fibrosis mutations lead to carboxyl-terminal fragments that highlight an early biogenesis step of the cystic fibrosis transmembrane conductance regulator. J. Biol. Chem. 275: 19577-19584 41 Ostedgaard L. S., Zeiher B. and Welsh M. J. (1999) Processing of CFTR bearing the P574H mutation differs from wild-type and deltaF508-CFTR. Login to comment 339 ABCC7 p.Ala559Thr (1995) A cystic fibrosis patient who is homozygous for the A559T mutation. Login to comment 343 ABCC7 p.Asn1303Lys et al. (1992) Incidence and expression of the N1303K mutation of the cystic fibrosis (CFTR) gene. Login to comment 345 ABCC7 p.Gly480Cys Nat. Struct. Mol. Biol. 12: 17-25 46 Smit L. S., Strong T. V., Wilkinson D. J., Macek M., Mansoura M. K., Wood D. L. et al. (1995) Missense mutation (G480C) in the CFTR gene associated with protein mislocalization but normal chloride channel activity. Login to comment 348 ABCC7 p.Gly551Asp J. Cyst. Fibros. 3: 183-190 48 Delaney S. J., Alton E. W., Smith S. N., Lunn D. P., Farley R., Lovelock P. K. et al. (1996) Cystic fibrosis mice carrying the missense mutation G551D replicate human genotype-phenotype correlations. Login to comment 350 ABCC7 p.Gly551Asp B., Dong J. Y. and Fischer H. (1999) Defective function of the cystic fibrosis-causing missense mutation G551D is recovered by genistein. Login to comment 360 ABCC7 p.Asp579Gly J. Biol. Chem. 277: 35896-35905 55 Picci L., Cameran M., Olante P., Zacchello F. and Scarpa M. (1999) Identification of a D579G homozygote cystic fibrosis patient with pancreatic sufficiency and minor lung involvement. Login to comment 362 ABCC7 p.Asp579Gly 13: 173 56 Salvatore D., Tomaiuolo R., Abate R., Vanacore B., Manieri S., Mirauda M. P. et al. (2004) Cystic fibrosis presenting as metabolic alkalosis in a boy with the rare D579G mutation. Login to comment