ABCC7 p.Ser1251Ala
| ClinVar: |
c.3752G>A
,
p.Ser1251Asn
D
, Pathogenic
|
| CF databases: |
c.3752G>A
,
p.Ser1251Asn
D
, CF-causing ; CFTR1: The nucleotide change is G to A at position 3884 and results in an amino acid change of the conserved serine by an asparagine (S1251N). The two unrelated German CF patients (17 and 19 years old) are pancreas insufficient and suffer from all typical signs of the disease. The mutation destroys recognition sites for RsaI and EarI. Digestion with RsaI results in five fragments for the normal (188, 95, 82 79, 29 bp) and four fragments for the mutant allele (267, 95, 82, 29 bp). The mutation was not found on further 67 German and 12 turkish non-[delta] CF chromosomes nor on 20 normal chromosomes. S1251N is associated with the haplotype 2-1-1-2 (XV2c-KM, 19-D9-J44) and with F508C.
|
| Predicted by SNAP2: | A: D (95%), C: D (95%), D: D (95%), E: D (95%), F: D (95%), G: D (95%), H: D (95%), I: D (95%), K: D (95%), L: D (95%), M: D (95%), N: N (78%), P: D (95%), Q: D (95%), R: D (95%), T: D (95%), V: D (95%), W: D (95%), Y: D (95%), |
| Predicted by PROVEAN: | A: N, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: N, P: D, Q: D, R: D, T: N, V: D, W: D, Y: D, |
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[hide] Therapeutic approaches to repair defects in deltaF... Adv Drug Deliv Rev. 2002 Dec 5;54(11):1395-408. Powell K, Zeitlin PL
Therapeutic approaches to repair defects in deltaF508 CFTR folding and cellular targeting.
Adv Drug Deliv Rev. 2002 Dec 5;54(11):1395-408., [PMID:12458151]
Abstract [show]
The deltaF508 mutation in the cystic fibrosis transmembrane regulator (CFTR) gene is the most common mutation in CF. The mutant CFTR protein is defective with respect to multiple functions including cAMP-regulated chloride conductance, nucleotide transport, and regulatory actions on other ion channels. Since the deltaF508 protein is also temperature-sensitive and unstable during translation and folding in the endoplasmic reticulum (ER), most of the nascent chains are targeted for premature proteolysis from the ER. This paper focuses on the events that occur in the ER during folding and reviews potential targets for therapeutic intervention.
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No. Sentence Comment
119 By studying Among the best-studied molecular chaperones are other CFTR mutations (D572A and S1251A), it was the 70-kDa heat shock proteins, including Hsp70 shown that these mutations were not sensitive to [40] and Hsc70.
X
ABCC7 p.Ser1251Ala 12458151:119:92
status: NEW[hide] Glycerol reverses the misfolding phenotype of the ... J Biol Chem. 1996 Jan 12;271(2):635-8. Sato S, Ward CL, Krouse ME, Wine JJ, Kopito RR
Glycerol reverses the misfolding phenotype of the most common cystic fibrosis mutation.
J Biol Chem. 1996 Jan 12;271(2):635-8., [PMID:8557666]
Abstract [show]
The common delta F508 mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) interferes with the biosynthetic folding of nascent CFTR polypeptides, leading to their retention and rapid degradation in an intracellular compartment proximal to the Golgi apparatus. Neither the pathway by which wild-type CFTR folds nor the mechanism by which the Phe508 deletion interferes with this process is well understood. We have investigated the effect of glycerol, a polyhydric alcohol known to stabilize protein conformation, on the folding of CFTR and delta F508 in vivo. Incubation of transient and stable delta F508 transfectants with 10% glycerol induced a significant accumulation of delta F508 protein bearing complex N-linked oligosaccharides, indicative of their transit to a compartment distal to the endoplasmic reticulum (ER). This accumulation was accompanied by an increase in mean whole cell cAMP activated chloride conductance, suggesting that the glycerol-rescued delta F508 polypeptides form functional plasma membrane CFTR channels. These effects were dose- and time-dependent and fully reversible. Glycerol treatment also stabilized immature (core-glycosylated) delta F508 and CFTR molecules that are normally degraded rapidly. These effects of glycerol were not due to a general disruption of ER quality control processes but appeared to correlate with the degree of temperature sensitivity of specific CFTR mutations. These data suggest a model in which glycerol serves to stabilize an otherwise unstable intermediate in CFTR biosynthesis, maintaining it in a conformation that is competent for folding and subsequent release from the ER quality control apparatus.
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No. Sentence Comment
91 Cells expressing the missense mutants D572A and S1251A and a mutant harboring a deletion of exon 13 (⌬EX13) were pulse-labeled with [35 S]Met and chased for 5 h in the presence or absence of glycerol (Fig. 3A).
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ABCC7 p.Ser1251Ala 8557666:91:48
status: NEW93 Thus, some mutations in all three major cytoplasmic domains of CFTR, including the first and second nucleotide binding domains (D572A and S1251A, respectively) as well as the "R" domain, can lead to a glycerol-insensitive ER retention phenotype, suggesting that glycerol treatment does not induce a general suppression of ER retention mechanisms.
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ABCC7 p.Ser1251Ala 8557666:93:48
status: NEWX
ABCC7 p.Ser1251Ala 8557666:93:138
status: NEW95 Processing of mutants K464R and K464A was inefficient by comparison with wild type and was enhanced by incubation in the presence of 10% glycerol, even after accounting for the unequal label present in the immature precursor in the presence of glycerol (Fig. 3B).
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ABCC7 p.Ser1251Ala 8557666:95:138
status: NEW