ABCMdb

ABCC7 p.Thr908Asn

None has been submitted yet.

Publications

PMID: 11278813 [PubMed] Hammerle MM et al: "Disease-associated mutations in the extracytoplasmic loops of cystic fibrosis transmembrane conductance regulator do not impede biosynthetic processing but impair chloride channel stability."

No. Sentence Comment

75 TABLE I Oligonucleotide primers used to generate mutations Mutation Primer S108F GGAAGAATCATAGCTTtCTATGACCCGGATAAC Y109C AGAATCATAGCTTCCTgTGACCCGGATAACAAG D110H ATCATAGCTTCCTATcACCCGGATAACAAGGAG P111A ATAGCTTCCTATGACgCGGATAACAAGGAGGAA P111L ATAGCTTCCTATGACCtGGATAACAAGGAGGAA E116K CCGGATAACAAGGAGaAACGCTCTATCGCGATT R117C GATAACAAGGAGGAAtGCTCTATCGCGATTTAT R117H GATAACAAGGAGGAACaCTCTATCGCGATTTAT R117L GATAACAAGGAGGAACtCTCTATCGCGATTTAT R117P GATAACAAGGAGGAACcCTCTATCGCGATTTAT E217G ATGGGGCTAATCTGGGgGTTGTTACAGGCGTCT T908N TATGCAGTGATTATCAaCAGCACCAGTTCGTAT P1013L GTCGCAGTTTTACAACtCTACATCTTTGTTGCA FIG. 2. Login to comment
91 Exceptions are S108F, which matures as efficiently as the wild type, and T908N, which matures even more efficiently. Login to comment
120 D, squares, E217G; circles, T908N; triangles, P1013L. Login to comment
153 The T908N mutation in EL4, the second of the two larger extracytoplasmic loops of CFTR, has a somewhat similar effect on the single channel behavior as those in EL1 that cause a very unstable open state. Login to comment
156 As seen in the T908N trace, there are in fact relatively long openings with several brief closings within to generate burstlike behavior. Login to comment
171 For example a nucleotide binding domain mutation, G551D, precludes virtually all TABLE II Relative charge transport capacity of mutants Mutants S108F Y109C D110H P111L P111A E116K R117H R117C R117L R117P E217G T908N P1013L Imutant/Iwt 100% 11 15 27 173 105 12 80 27 5 11 10 48 170 FIG. 5. Login to comment
190 The T908N mutation in EL4, which is novel in that it results in the introduction of an additional consensus site for N-glycosylation that is used (17), also alters channel gating. Login to comment

PMID: 11443282 [PubMed] Hammerle MM et al: "A novel CFTR disease-associated mutation causes addition of an extra N-linked oligosaccharide."

No. Sentence Comment

3 This substitution (T908N) creates a consensus sequence (N X S=T) for addition of an N-linked oligosaccharide chain near the C-terminal end of EL4. Login to comment
5 However, the T908N site is used, even though it is within four residues of the predicted membrane interface and the oligosaccharide chain added binds calnexin, a resident chaperone of the ER membrane. Login to comment
13 However, while analyzing the functional impact of missense mutations in the putative extracytoplasmic loops (ELs) of the protein [7], we realized that one (T908N) created a consensus sequence (N X S=T) for N-glycosylation. Login to comment
20 BHK cells stably expressing T908N-CFTR were similarly established. Login to comment
23 Tel.: 480-301-6206; Fax: 480-301-7017; E-mail: riordan@mayo.edu N900D, T908N or T910N to produce a CFTR with different numbers or no consensus site for glycosylation on extracytoplasmic loop 4. Login to comment
46 Single channel records Microsomal vesicles were isolated from BHK cells expressing wildtype and T908N CFTR and phosphorylated with protein kinase A [17]. Login to comment
52 Reconstruction and expression of the T908N variant in BHK cells resulted in the synthesis of a protein which ran with reduced mobility in SDS-PAGE (Figure 1B) consistent with the possibility that this additional N-glycosylation site had been used. Login to comment
54 The sialidase treatment increased the mobility of both the wild-type and the T908N variant substantially, indicating that the oligosaccharide chains are highly sialylated. Login to comment
55 After N-glycosidase F treatment the mobility is increased further and the deglycosylated form of both the wild-type and T908N migrate to the same position. Login to comment
57 The difference in mobility between wild-type and T908N was entirely eliminated after cells were grown in presence of the inhibitor. Login to comment
60 (A) Sketch of CFTR topology indicating position of T908N relative to the membrane and native glycosylation sites at N894 and N900. Login to comment
61 (B) Cells stably expressing wild type and T908N-CFTR were lysed in NP-40 lysis buffer (see Materials and methods). Login to comment
65 Cells expressing wild-type and T908N-CFTR were pulse labeled and chased as described in Methods. oligosaccharyl transferase and is an acceptor of an N-linked oligosaccharide chain. Login to comment
69 Conversion of precursor to product occurs with low efficiency ($ 30%) but this also is similar with wild-type and the T908N variant. Login to comment
70 Hence the additional oligosaccharide in T908N does not have a profound effect on the biosynthetic processing of CFTR. Login to comment
89 As already noted in Figure 1 the T908N variant in the wild-type background has substantially decreased mobility. Login to comment
98 T908N reduces the rate of 36 Cl7 efflux and alters both the single channel gating kinetics and conductance of CFTR. Login to comment
108 As shown in Figure 1B, removal of sialic acid from complex glycosylated CFTR results in a higher mobility of wild-type and T908N. Login to comment
114 Similar amounts of calnexin were detected in CFTR immunoprecipitates containing wild-type and T908N, and 894N and 900N alone whereas much less was detected when single oligosaccharide chains were present at 908N and especially at 910N (Figure 3). Login to comment
116 To assess how the presence of a third oligosaccharide chain influences CFTR function, the rate of 36 Cl7 efflux from cells expressing the T908N variant was compared with wild-type and was found to be reduced about 50% (Figure 4A). Login to comment
119 Thus both measures of the T908N CFTR chloride channel indicate that while still active, it is substantially altered from the wild-type. Login to comment
120 Discussion Although all types of mutations have been detected in the CFTR gene of patients with cystic fibrosis, T908N is the only example of a single residue substitution that introduces a consensus site for glycosylation. Login to comment

PMID: 17003641 [PubMed] Keiles S et al: "Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis."

No. Sentence Comment

112 However, this patient also carries a T908N mutation in the CFTR gene. Login to comment
116 Patients With CFTR and PRSS1 Mutations CFTR Mutation 1 CFTR Mutation 2 PRSS1 Mutation 1 PRSS1 Mutation 2 No. of Patients 5T E79K 1 5T R122H 1 2789+17 C9T C139S 1 deltaF508 N29I 1 deltaF508 Q1352H G208A G208A 1 G551D R122H 1 T908N IVS4-8 C9T IVS4-11 C9T 1 Total patients 7 CFTR mutations in boldface would not have been detected by the ACOG/ACMG mutation panel. Login to comment

PMID: 19307599 [PubMed] Glozman R et al: "N-glycans are direct determinants of CFTR folding and stability in secretory and endocytic membrane traffic."

No. Sentence Comment

263 In accord, with the localized effect of the glycan chain, partial reversion of the expression and folding defect of the 900D- and 2D-CFTR was observed by introducing a validated glycosylation site (T908N) in the fourth extracellular loop (Hammerle et al., 2000; Fig. S5). Login to comment

PMID: 20059485 [PubMed] Dorfman R et al: "Do common in silico tools predict the clinical consequences of amino-acid substitutions in the CFTR gene?"

No. Sentence Comment

64 Mutations in the CFTR gene grouped by clinical category Cystic fibrosis CFTR-related disease No disease T338I D614G L320V V920L L90S M470V H199R S1251N I203M G550R P111A I148T Q1291H R560K L1388Q L183I R170H I1027T S549R D443Y P499A L1414S T908N R668C S549N A455E E1401K Q151K G27E I1234L Y563N R347P C866R S1118C P1290S R75Q A559T V520F P841R M469V E1401G P67L G85E S50Y E1409K R933G G458V G178R Y1032C R248T I980K G85V V392G L973P L137H T351S R334W I444S V938G R792G R560T R555G L1339F D1305E P574H V1240G T1053I D58G G551D L1335P I918M F994C S945L L558S F1337V R810G D1152H G1247R P574S R766M D579G W1098R H949R F200I R352Q L1077P K1351E M244K L206W M1101K D1154G L375F N1303K R1066C E528D D110Y R347H R1070Q A800G P1021S S549K A1364V V392A damaging` (is supposed to affect protein function or structure) and 'probably damaging` (high confidence of affecting protein function or structure). Login to comment

PMID: 10923036 [PubMed] Claustres M et al: "Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France."

No. Sentence Comment

152 Twenty-four non F508del mutations were found associated with the 9T allele: 394delTT, L90S, D110H, R117G, 621+1G>T, V232D, A455E, G542X, R851L, T908N, 2789+5G>A, 2896insAG, H939R, 3007delG, I980K, I1027T, R1066H, A1067T, D1154G, 3737delA, R74W+D1270N, N1303I, N1303K, D1377H. Login to comment

PMID: 23248597 [PubMed] Kim SJ et al: "Mechanisms of CFTR Folding at the Endoplasmic Reticulum."

No. Sentence Comment

96 The CF mutation T908N, however, creates a glycosylation site that is recognized by OST even though it is only four-residues from the predicted N-terminus of TM8. Login to comment