ABCC7 p.Gln1412*
| ClinVar: |
c.4234C>T
,
p.Gln1412*
?
, not provided
|
| CF databases: |
c.4234C>T
,
p.Gln1412*
D
, CF-causing
|
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[hide] C-terminal truncations destabilize the cystic fibr... J Biol Chem. 1999 Jul 30;274(31):21873-7. Haardt M, Benharouga M, Lechardeur D, Kartner N, Lukacs GL
C-terminal truncations destabilize the cystic fibrosis transmembrane conductance regulator without impairing its biogenesis. A novel class of mutation.
J Biol Chem. 1999 Jul 30;274(31):21873-7., 1999-07-30 [PMID:10419506]
Abstract [show]
Defective cAMP-stimulated chloride conductance of the plasma membrane of epithelial cell is the hallmark of cystic fibrosis (CF) and results from mutations in the cystic fibrosis transmembrane conductance regulator, CFTR. In the majority of CF patients, mutations in the CFTR lead to its misfolding and premature degradation at the endoplasmic reticulum (ER). Other mutations impair the cAMP-dependent activation or the ion conductance of CFTR chloride channel. In the present work we identify a novel mechanism leading to reduced expression of CFTR at the cell surface, caused by C-terminal truncations. The phenotype of C-terminally truncated CFTR, representing naturally occurring premature termination and frameshift mutations, were examined in transient and stable heterologous expression systems. Whereas the biosynthesis, processing, and macroscopic chloride channel function of truncated CFTRs are essentially normal, the degradation rate of the mature, complex-glycosylated form is 5- to 6-fold faster than the wild type CFTR. These experiments suggest that the C terminus has a central role in maintaining the metabolic stability of the complex-glycosylated CFTR following its exit from the ER and provide a plausible explanation for the severe phenotype of CF patients harboring C-terminal truncations.
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19 Premature stop codons were as follows: Q1412X (A. Wallace and M. Tassabehji; ⌬70); S1455X and L1399X (⌬26 and ⌬82, respectively).
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ABCC7 p.Gln1412* 10419506:19:39
status: NEW86 RESULTS AND DISCUSSION Analysis of mutations found in the Cystic Fibrosis Genetic Consortium Database revealed that the shortest truncation, which manifests in CF with pancreatic insufficiency and recurrent pulmonary infection, is Q1412X (the genotype and clinical symptoms of the patient were kindly provided by C. J. Taylor, University of Sheffield, UK).
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ABCC7 p.Gln1412* 10419506:86:231
status: NEW[hide] Genotype and phenotype in cystic fibrosis. Respiration. 2000;67(2):117-33. Zielenski J
Genotype and phenotype in cystic fibrosis.
Respiration. 2000;67(2):117-33., [PMID:10773783]
Abstract [show]
Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene which encodes a protein expressed in the apical membrane of exocrine epithelial cells. CFTR functions principally as a cAMP-induced chloride channel and appears capable of regulating other ion channels. Besides the most common mutation, DeltaF508, accounting for about 70% of CF chromosomes worldwide, more than 850 mutant alleles have been reported to the CF Genetic Analysis Consortium. These mutations affect CFTR through a variety of molecular mechanisms which can produce little or no functional CFTR at the apical membrane. This genotypic variation provides a rationale for phenotypic effects of the specific mutations. The extent to which various CFTR alleles contribute to clinical variation in CF is evaluated by genotype-phenotype studies. These demonstrated that the degree of correlation between CFTR genotype and CF phenotype varies between its clinical components and is highest for the pancreatic status and lowest for pulmonary disease. The poor correlation between CFTR genotype and severity of lung disease strongly suggests an influence of environmental and secondary genetic factors (CF modifiers). Several candidate genes related to innate and adaptive immune response have been implicated as pulmonary CF modifiers. In addition, the presence of a genetic CF modifier for meconium ileus has been demonstrated on human chromosome 19q13.2. The phenotypic spectrum associated with mutations in the CFTR gene extends beyond the classically defined CF. Besides patients with atypical CF, there are large numbers of so-called monosymptomatic diseases such as various forms of obstructive azoospermia, idiopathic pancreatitis or disseminated bronchiectasis associated with CFTR mutations uncharacteristic for CF. The composition, frequency and type of CFTR mutations/variants parallel the spectrum of CFTR-associated phenotypes, from classic CF to mild monosymptomatic presentations. Expansion of the spectrum of disease associated with the CFTR mutant genes creates a need for revision of the diagnostic criteria for CF and a dilemma for setting nosologic boundaries between CF and other diseases with CFTR etiology.
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No. Sentence Comment
99 These are usually nonsense or frameshift mutations (Q1412X, 4326delTC, 4279insA) causing a 70to 100-bp truncation of the C-terminus of the CFTR [28] and associated with severe CF presentation.
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ABCC7 p.Gln1412* 10773783:99:52
status: NEW[hide] Towards the pharmacogenomics of cystic fibrosis. Pharmacogenomics. 2002 Jan;3(1):75-87. Sangiuolo F, D'Apice MR, Bruscia E, Lucidi V, Novelli G
Towards the pharmacogenomics of cystic fibrosis.
Pharmacogenomics. 2002 Jan;3(1):75-87., [PMID:11966405]
Abstract [show]
Cystic fibrosis (CF) is the most common lethal recessive genetic disease affecting children in Europe and the US. CF is a multiorgan disease and may present a variety of clinical symptoms, like chronic obstructive lung disease, exocrine pancreatic insufficiency (PI) and elevated sweat chloride concentration. CF mutations have also been found in other related clinical diseases such as congenital bilateral absence of the vas deferens (CBAVD), disseminated bronchiectasis and chronic pancreatitis. These clinical overlaps pose etiopathogenetic, diagnostic and therapeutic questions. Despite stunning advances in genomic technologies and drug discovery, drug therapy often improves disease symptoms but does not cure the disease. One of the main causes of this failure in CF cure may be attributable to genetic variability and to the scarce knowledge of CF biochemistry. Therefore, knowing the genotype of a patient might help improve drug efficacy, reduce toxicity and suggests innovative genomic-based therapy approaches.
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116 Q1412X, 4326delTC, 4279insA Severe Functional but unstable CFTR at the apical membrane See text Modified from [56,102].
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ABCC7 p.Gln1412* 11966405:116:0
status: NEW[hide] Splice mutation 1811+1.6kbA>G causes severe cystic... J Med Genet. 2002 Nov;39(11):e73. Reboul MP, Bieth E, Fayon M, Biteau N, Barbier R, Dromer C, Desgeorges M, Claustres M, Bremont F, Lacombe D, Iron A
Splice mutation 1811+1.6kbA>G causes severe cystic fibrosis with pancreatic insufficiency: report of 11 compound heterozygous and two homozygous patients.
J Med Genet. 2002 Nov;39(11):e73., [PMID:12414835]
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157 This is the case for nonsense and frameshift mutations always associated with severe CF with PI: they come into class I (for instance, G542X) when they lead to an absence of functional CFTR and into the "new" class V (for instance, Q1412X) when they cause the presence of a functional but unstable CFTR at the apical membrane.
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ABCC7 p.Gln1412* 12414835:157:232
status: NEW[hide] Effects of C-terminal deletions on cystic fibrosis... Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1937-42. Epub 2003 Feb 10. Ostedgaard LS, Randak C, Rokhlina T, Karp P, Vermeer D, Ashbourne Excoffon KJ, Welsh MJ
Effects of C-terminal deletions on cystic fibrosis transmembrane conductance regulator function in cystic fibrosis airway epithelia.
Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1937-42. Epub 2003 Feb 10., 2003-02-18 [PMID:12578973]
Abstract [show]
To better understand the function of the conserved C terminus of the cystic fibrosis (CF) transmembrane conductance regulator, we studied constructs containing deletions in the C-terminal tail. When expressed in well differentiated CF airway epithelia, each construct localized predominantly to the apical membrane and generated transepithelial Cl(-) current. The results suggested that neither the C-terminal PSD-95/Discs-large/ZO-1 (PDZ)-interacting motif nor other C-terminal sequences were absolutely required for apical expression in airway epithelia. Surprisingly, deleting an acidic cluster near the C terminus reduced both channel opening rate and transepithelial Cl(-) transport, indicating that it influences channel gating. These results may help explain the relative paucity of CF-associated mutations in the C terminus.
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7 Deletion of 26 C-terminal residues by the S1455X mutation was associated with elevated sweat Cl- concentrations, but not other manifestations of CF (4), whereas deletion of the last 70 residues by the Q1412X mutation caused CF (C. J. Taylor, personal communication).
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ABCC7 p.Gln1412* 12578973:7:201
status: NEW117 In addition, whole-cell patch-clamp studies of BHK-21 and IB3-1 cells reported that the S1455X mutation had no effect on current, but the Q1412X mutation reduced current by 90% (4, 19).
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ABCC7 p.Gln1412* 12578973:117:138
status: NEW249 In contrast, the much longer Q1412X deletion appeared to cause CF.
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ABCC7 p.Gln1412* 12578973:249:29
status: NEW[hide] The phenotypic consequences of CFTR mutations. Ann Hum Genet. 2003 Sep;67(Pt 5):471-85. Rowntree RK, Harris A
The phenotypic consequences of CFTR mutations.
Ann Hum Genet. 2003 Sep;67(Pt 5):471-85., [PMID:12940920]
Abstract [show]
Cystic fibrosis is a common autosomal recessive disorder that primarily affects the epithelial cells in the intestine, respiratory system, pancreas, gall bladder and sweat glands. Over one thousand mutations have currently been identified in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene that are associated with CF disease. There have been many studies on the correlation of the CFTR genotype and CF disease phenotype; however, this relationship is still not well understood. A connection between CFTR genotype and disease manifested in the pancreas has been well described, but pulmonary disease appears to be highly variable even between individuals with the same genotype. This review describes the current classification of CFTR mutation classes and resulting CF disease phenotypes. Complex disease alleles and modifier genes are discussed along with alternative disorders, such as disseminated bronchiectasis and pancreatitis, which are also thought to result from CFTR mutations.
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No. Sentence Comment
85 The shortest truncation reported that caused CF with pancreatic insufficiency and recurrent pulmonary infection is Q1412X, that lacks 70 amino acids (CF Genetic Analysis Consortium).
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ABCC7 p.Gln1412* 12940920:85:115
status: NEW[hide] Genetics of cystic fibrosis. Semin Respir Crit Care Med. 2003 Dec;24(6):629-38. Gallati S
Genetics of cystic fibrosis.
Semin Respir Crit Care Med. 2003 Dec;24(6):629-38., [PMID:16088579]
Abstract [show]
Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which encodes a protein expressed in the apical membrane of exocrine epithelial cells. CFTR functions principally as a cyclic adenosine monophosphate (cAMP)-induced chloride channel and appears capable of regulating other ion channels. Mutations affect CFTR through a variety of molecular mechanisms, which can produce little or no functional gene product at the apical membrane. More than 1000 different disease-causing mutations within the CFTR gene have been described. The potential of a mutation to contribute to the phenotype depends on its type, localization in the gene, and the molecular mechanism as well as on interactions with secondary modifying factors. Genetic testing can confirm a clinical diagnosis of CF and can be used for infants with meconium ileus, for carrier detection in individuals with positive family history and partners of proven CF carriers, and for prenatal diagnostic testing if both parents are carriers. Studies of clinical phenotype in correlation with CFTR genotype have revealed a very complex relationship demonstrating that some phenotypic features are closely determined by the underlying mutations, whereas others are modulated by modifier genes, epigenetic mechanisms, and environment.
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60 ClassVI: Decreased Stability Nonsense and frameshift mutations (e.g., Q1412X, 4326delTC, 4279insA) causing a 70to 100-bp truncation of the C-terminus of the CFTR lead to a marked instability of an otherwise fully processed and functional variant,24 and as a consequence to a severe CF presentation.
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ABCC7 p.Gln1412* 16088579:60:70
status: NEW[hide] The relevance of sweat testing for the diagnosis o... Clin Biochem Rev. 2005 Nov;26(4):135-53. Mishra A, Greaves R, Massie J
The relevance of sweat testing for the diagnosis of cystic fibrosis in the genomic era.
Clin Biochem Rev. 2005 Nov;26(4):135-53., [PMID:16648884]
Abstract [show]
Cystic fibrosis (CF) is the most common inherited disorder of childhood. The diagnosis of CF has traditionally been based on clinical features with confirmatory evidence by sweat electrolyte analysis. Since 1989 it has been possible to also use gene mutation analysis to aid the diagnosis. Cloning of the cystic fibrosis transmembrane conductance regulator (CFTR) gene has advanced our understanding of CF, in particular the molecular basis of an expanded CF phenotype. However, because there are over 1000 mutations and 200 polymorphisms, many without recognised effects on CFTR, the molecular diagnosis can be troublesome. This has necessitated measurement of CFTR function with renewed interest in the sweat test. This review provides an overview of the clinical features of CF, the diagnosis and complex genetics. We provide a detailed discussion of the structure and function of CFTR and the classification of CFTR mutations. Sweat electrolyte analysis is discussed, from the physiology of sweating to the rigours of a properly performed sweat test and its interpretation. With this information it is possible to understand the relevance of the sweat test in the genomic era.
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121 Predicted mutations in the CFTR promoter can have similar effects by reducing the level of transcription.2,67 Class VI: Reduced Protein Stability Mutations in this novel class include protein stability mutants which cause lability of the CFTR protein, such as mutations resulting in absence of the 70-98 residues of the CFTR C-terminus.70,79 Although the C-terminus is not required for the biogenesis and chloride channel function of CFTR, it is indispensable for maintaining the stability of complex-glycosylated CFTR.2 The shortest truncation reported that causedCFwithpancreaticinsufficiencyandrecurrentpulmonary infection is Q1412X which lacks 70 amino acids.
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ABCC7 p.Gln1412* 16648884:121:629
status: NEW[hide] Diagnosis of cystic fibrosis. Clin Rev Allergy Immunol. 2008 Dec;35(3):100-6. Voter KZ, Ren CL
Diagnosis of cystic fibrosis.
Clin Rev Allergy Immunol. 2008 Dec;35(3):100-6., [PMID:18506640]
Abstract [show]
Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene that results in abnormal viscous mucoid secretions in multiple organs and whose main clinical features are pancreatic insufficiency and chronic endobronchial infection. Although it was initially defined and diagnosed based on clinical features and sweat chloride measurement, an in vivo method of assessing CFTR function, the discovery of the CFTR gene in 1989 revealed a broad spectrum of CF phenotypes associated with specific CFTR gene mutations. In this article, we will review the indications for sweat testing, alternative techniques to diagnose CF, and the approach to patients with an ambiguous or indeterminate diagnosis of CF.
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114 Figure reproduced from Ref. [6], with permission Table 7 Classes of CFTR gene mutations associated with CF disease Mutation class Mechanism of action Examples I Absence of protein synthesis because of a stop codon in the gene G542X II Improper folding and processing ΔF508 III Reduced response to regulatory molecules G551D IV Reduce ion conductance R117H V Decreased protein production due to splice defects or promoter mutations 3,849+10 kb C→T VI Decreased protein stability Q1412X 104 measurement of transepithelial ion flow in the nasal mucosa [28-30].
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ABCC7 p.Gln1412* 18506640:114:491
status: NEW[hide] Cystic fibrosis: exploiting its genetic basis in t... Pharmacol Ther. 2010 Feb;125(2):219-29. Epub 2009 Nov 10. Kreindler JL
Cystic fibrosis: exploiting its genetic basis in the hunt for new therapies.
Pharmacol Ther. 2010 Feb;125(2):219-29. Epub 2009 Nov 10., [PMID:19903491]
Abstract [show]
Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel expressed in epithelial cells throughout the body. In the lungs, absence or dysfunction of CFTR results in altered epithelial salt and water transport eventuating in impaired mucociliary clearance, chronic infection and inflammation, and tissue damage. CF lung disease is the major cause of morbidity and mortality in CF despite the many therapies aimed at reducing it. However, recent technological advances combined with two decades of research driven by the discovery of the CFTR gene have resulted in the development and clinical testing of novel therapies aimed at the principal underlying defect in CF, thereby ushering in a new age of therapy for CF.
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405 Table 1 Classification of CFTR mutations. Class Mutation example Cellular/molecular phenotype I W1282X Absent CFTR production due to nonsense mutations, frameshift mutations, or abnormal mRNA splicing II ΔF508 Improper intracellular processing of CFTR with less than normal amounts of CFTR protein at the apical plasma membrane III G551D Defective regulation of CFTR channels at the apical plasma membrane IV R117H Defective permeation of anions through CFTR channels at the apical plasma membrane V 3849+10KbCNT Reduced synthesis of normal CFTR VI Q1412X Altered apical membrane residence time of CFTR channels with truncated c-termini 4.
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ABCC7 p.Gln1412* 19903491:405:555
status: NEW[hide] Cystic Fibrosis: therapies targeting specific gene... Paediatr Respir Rev. 2012 Dec;13(4):215-9. doi: 10.1016/j.prrv.2012.04.003. Epub 2012 May 9. Thursfield RM, Davies JC
Cystic Fibrosis: therapies targeting specific gene defects.
Paediatr Respir Rev. 2012 Dec;13(4):215-9. doi: 10.1016/j.prrv.2012.04.003. Epub 2012 May 9., [PMID:23069118]
Abstract [show]
Cystic Fibrosis (CF) is caused by a large number of mutations in the CFTR gene, leading to specific classes of protein defects. This review discusses these classes, an understanding of which has paved the way for novel treatment strategies. The progress in this field, through from basic research to, in one case, application for license, is described.
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42 Arg117His previously termed R117H] V Splicing defect: leads to decreased amount of CFTR protein at the cell surface [eg 3849+10 kb C>T] VI Functional but unstable with decreased half life at the cell surface [eg Gln1412X previously termed Q1412X] R.M. Thursfield, J.C. Davies / Paediatric Respiratory Reviews (2012) 215-219216 difference (nPD) measurement.
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ABCC7 p.Gln1412* 23069118:42:239
status: NEW[hide] Keratin K18 increases CFTR surface expression by b... J Biol Chem. 2012 Oct 8. Duan Y, Sun Y, Zhang F, Zhang WK, Wang D, Wang Y, Cao X, Hu W, Xie C, Cuppoletti J, Magin TM, Wang H, Wu Z, Li N, Huang P
Keratin K18 increases CFTR surface expression by binding to its C-terminal hydrophobic patch.
J Biol Chem. 2012 Oct 8., [PMID:23045527]
Abstract [show]
Malfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) leads to cystic fibrosis, but the regulation of CFTR is not fully understood. Here, we identified the intermediate filament protein keratin K18 (K18) as a CFTR binding protein by various approaches. We mapped a highly conserved hydrophobic patch (F1413LVI) in the CFTR carboxy-terminus, known to determine plasmalemmal CFTR stability, as the K18 binding site. On the other hand, the C-terminal tail of K18 was found to be a critical determinant for binding CFTR. Overexpression of K18 in cells robustly increased the surface expression of wild-type CFTR, whereas depletion of K18 through RNA interference specifically diminished it. K18 binding increased the surface expression of CFTR by accelerating its apical recycling rate without altering CFTR's biosynthesis, maturation or internalization. Importantly, CFTR surface expression was markedly reduced in duodenal and gallbladder epithelia of K18-/- mice. Taken together, our results suggest that K18 increases the cell surface expression of CFTR by interacting with CFTR's C-terminal hydrophobic patch. These findings offer novel insights into the regulation of CFTR and suggest that K18 and its dimerization partner K8 may be modifier genes in cystic fibrosis.
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23 Interestingly, clinical studies suggest that the deletion of CFTR`s C-terminal 26 residues by the S1455X mutation elevates the chloride concentration in sweat without producing any other CF symptoms, while the deletion of the C-terminal 69 residues by Q1412X mutation results in severe CF (8-10).
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ABCC7 p.Gln1412* 23045527:23:252
status: NEW238 It is possible that mutation Q1412X in CFTR, but not mutation S1455X, disrupts the K18 binding site and thus leads to the loss of plasmalemmal CFTR in epithelia and causes severe CF in patients.
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ABCC7 p.Gln1412* 23045527:238:29
status: NEW17 Interestingly, clinical studies suggest that the deletion of the CFTR C-terminal 26 residues by the S1455X mutation elevates the chloride concentration in sweat without producing any other CF symptoms, whereas the deletion of the C-terminal 69 residues by the Q1412X mutation results in severe CF (8-10).
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ABCC7 p.Gln1412* 23045527:17:260
status: NEW291 It is possible that mutation Q1412X in CFTR, but not mutation S1455X, disrupts the K18-binding site and thus leads to the loss of plasmalemmal CFTR in epithelia and causes severe CF in patients.
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ABCC7 p.Gln1412* 23045527:291:29
status: NEW[hide] A haplotype framework for cystic fibrosis mutation... J Mol Diagn. 2006 Feb;8(1):119-27. Elahi E, Khodadad A, Kupershmidt I, Ghasemi F, Alinasab B, Naghizadeh R, Eason RG, Amini M, Esmaili M, Esmaeili Dooki MR, Sanati MH, Davis RW, Ronaghi M, Thorstenson YR
A haplotype framework for cystic fibrosis mutations in Iran.
J Mol Diagn. 2006 Feb;8(1):119-27., [PMID:16436643]
Abstract [show]
This is the first comprehensive profile of cystic fibrosis transmembrane conductance regulator (CFTR) mutations and their corresponding haplotypes in the Iranian population. All of the 27 CFTR exons of 60 unrelated Iranian CF patients were sequenced to identify disease-causing mutations. Eleven core haplotypes of CFTR were identified by genotyping six high-frequency simple nucleotide polymorphisms. The carrier frequency of 2.5 in 100 (1 in 40) was estimated from the frequency of heterozygous patients and suggests that contrary to popular belief, cystic fibrosis may be a common, under-diagnosed disease in Iran. A heterogeneous mutation spectrum was observed at the CFTR locus in 60 cystic fibrosis (CF) patients from Iran. Twenty putative disease-causing mutations were identified on 64 (53%) of the 120 chromosomes. The five most common Iranian mutations together represented 37% of the expected mutated alleles. The most frequent mutation, DeltaF508 (p.F508del), represented only 16% of the expected mutated alleles. The next most frequent mutations were c.1677del2 (p.515fs) at 7.5%, c.4041C>G (p.N1303K) at 5.6%, c.2183AA>G (p.684fs) at 5%, and c.3661A>T (p.K1177X) at 2.5%. Three of the five most frequent Iranian mutations are not included in a commonly used panel of CF mutations, underscoring the importance of identifying geographic-specific mutations in this population.
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111 of Patients Total alleles* Associated haplotype Global distributionHom Het Exon 1 c.134TϾC M1T 1 1 Rare Exon 3 c.386GϾA G85E 1 1 Global Exon 4 c.460GϾC D110H 1 1 H2 Europe Exon 7 c.1132CϾT R334W 1 1 H2 Global Exon 7 c.1145CϾT T338I 1 1 Europe Intron 9 c.1525-1GϾA Mis-splicing 1 1 H8 Pakistan Exon 10 c.1529CϾG S466X 1 2 H4 Germany Exon 10 c.1531CϾT L467F 1 1 Rare Exon 10 c.1649TϾC I506T 1 2 H8 Lebanon Exon 10 c.1652del3† ⌬F508 6 7 19 H5 Global Exon 10 c.1677delTA 515fs 4 1 9 H1 Europe Exon 11 c.1756GϾT G542X 1 1 H5 Global Exon 12 c.1821CϾA Y563X 2 2 Europe Exon 13 c.2183AAϾG 684fs 3 6 H3 Europe Exon 17a c.3170CϾT P1013L 1 1 Turkey Exon 19 c.3616CϾT R1162X 2 2 H2 Germany Exon 19 c.3661AϾT K1177X 1 1 3 H2 Bahrain Intron 20 c.4005ϩ1GϾA Mis-splicing 1 2 H2 Europe Exon 21 c.4041CϾG N1303K 3 1 7 H5 Global Exon 23 c.4363CϾT Q1412X 1 1 Rare *A total of 64 (53%) of the 120 expected alleles were observed.
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ABCC7 p.Gln1412* 16436643:111:956
status: NEW[hide] SSCP/heteroduplex analysis. Methods Mol Biol. 2002;187:151-63. Wallace AJ
SSCP/heteroduplex analysis.
Methods Mol Biol. 2002;187:151-63., [PMID:12013742]
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204 Also note how Q1412X gives rise only to a SSCP shift.
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ABCC7 p.Gln1412* 12013742:204:14
status: NEW[hide] Mutation characterization of CFTR gene in 206 Nort... Hum Mutat. 1996;8(4):340-7. Hughes DJ, Hill AJ, Macek M Jr, Redmond AO, Nevin NC, Graham CA
Mutation characterization of CFTR gene in 206 Northern Irish CF families: thirty mutations, including two novel, account for approximately 94% of CF chromosomes.
Hum Mutat. 1996;8(4):340-7., [PMID:8956039]
Abstract [show]
A variety of mutation detection techniques, including restriction endonuclease digestion, allele specific oligonucleotides, and automated fluorescent sequencing, were used in the identification of 15 CFTR mutations representing 86.7% of CF chromosomes in 206 Northern Irish cystic fibrosis (CF) families. A systematic analysis of the 27 exons and intron/exon boundaries of the CFTR gene was performed using denaturing gradient gel electrophoresis (DGGE) in an attempt to characterise the 55 unknown CF mutations in 51 patients. Twenty different mutations were detected by DGGE on 30 chromosomes accounting for a further 7.3% of CF alleles. Fifteen of these mutations had not previously been found in Northern Ireland, and two are novel, M1I(G > T) and V562L. In total, 30 CFTR mutations account for 93.9% of the 412 Northern Irish CF chromosomes tested. The three major CF mutations in Northern Ireland are delta F508, G551D, and R117H with respective frequencies of 68.0%, 5.1%, and 4.1%. The efficacy of the DGGE technique was proven by the detection of 77 out of 77 control variants from all the CFTR exons. DGGE is a highly efficient and sensitive method for mutation screening especially in large genes where the mutation spectrum is known to be heterogeneous.
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84 4048insCC, Q1313X E1371X Q1412X 4279insA 4521 G or A (p) S1196X, S1235R 10-60 20-80 20-80 0-50 20-70 20-70 20-70 20-70 20-70 10-60 20-70 20-70 0-50 20-80 20-80 20-80 20-80 20-70 20-70 20-80 20-80 20-70 20-70 20-70 20-70 20-70 20-70 20-80 20-70 20-70 40-80 75 75 150 75 150 150 150 75 150 150 150 75 150 75 75 75 150 150 150 95 150 150 150 150 150 150 150 150 150 150 150 9 9 4.5 6.5 4 4 4.5 7.5 4 5 4 7.5 4 7 7 7 4 4 4 6.5 4 4 3.5 4 4 5 4 6.5 4.5 4 4 ^Allmutationshave been reported to the CysticFibrosis Genetic AnalysisConsortium.The five polymorphisms are marked with a p in parenthesis.
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ABCC7 p.Gln1412* 8956039:84:25
status: NEW[hide] CFTR mutations spectrum and the efficiency of mole... PLoS One. 2014 Feb 26;9(2):e89094. doi: 10.1371/journal.pone.0089094. eCollection 2014. Zietkiewicz E, Rutkiewicz E, Pogorzelski A, Klimek B, Voelkel K, Witt M
CFTR mutations spectrum and the efficiency of molecular diagnostics in Polish cystic fibrosis patients.
PLoS One. 2014 Feb 26;9(2):e89094. doi: 10.1371/journal.pone.0089094. eCollection 2014., [PMID:24586523]
Abstract [show]
Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane regulator gene (CFTR). In light of the strong allelic heterogeneity and regional specificity of the mutation spectrum, the strategy of molecular diagnostics and counseling in CF requires genetic tests to reflect the frequency profile characteristic for a given population. The goal of the study was to provide an updated comprehensive estimation of the distribution of CFTR mutations in Polish CF patients and to assess the effectiveness of INNOLiPA_CFTR tests in Polish population. The analyzed cohort consisted of 738 patients with the clinically confirmed CF diagnosis, prescreened for molecular defects using INNOLiPA_CFTR panels from Innogenetics. A combined efficiency of INNOLiPA CFTR_19 and CFTR_17_TnUpdate tests was 75.5%; both mutations were detected in 68.2%, and one mutation in 14.8% of the affected individuals. The group composed of all the patients with only one or with no mutation detected (109 and 126 individuals, respectively) was analyzed further using a mutation screening approach, i.e. SSCP/HD (single strand conformational polymorphism/heteroduplex) analysis of PCR products followed by sequencing of the coding sequence. As a result, 53 more mutations were found in 97 patients. The overall efficiency of the CF allele detection was 82.5% (7.0% increase compared to INNOLiPA tests alone). The distribution of the most frequent mutations in Poland was assessed. Most of the mutations repetitively found in Polish patients had been previously described in other European populations. The most frequent mutated allele, F508del, represented 54.5% of Polish CF chromosomes. Another eight mutations had frequencies over 1%, 24 had frequencies between 1 and 0.1%; c.2052-2053insA and c.3468+2_3468+3insT were the most frequent non-INNOLiPA mutations. Mutation distribution described herein is also relevant to the Polish diaspora. Our study also demonstrates that the reported efficiency of mutation detection strongly depends on the diagnostic experience of referring health centers.
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60 The c.1116+2T.A (no chloride data available) was in trans with Q1412X; for the c.2817_2820delTACTC (PS; normal chloride values: 33 and 52 mmol/L), no second mutation was identified.
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ABCC7 p.Gln1412* 24586523:60:63
status: NEW71 Exon / intron (legacy) Exon / intron (Ensembl) Protein change SVM value cDNA (HGVS nomenclature) gDNA (cDNA +132 bp) Number of PL CF chromosomes Reference a Mutations in trans Pathogenic mutations 1 1 L15Ffs10X c.43delC 175delC 1 CFMDB 1717-1G.A 2 2 G27V 21.92 c.80G.T 212G.T 1 Novel F508del 2 2 S18RfsX16 c.54-5940_273 +10250del21kb exon2,3del21kb 66 IL19 various CF mutations i2 i2 IVS2_Donor c.164+1G.A 296+1G.A 3 CFMDB various CF mutations 3 3 G85E 22.61 c.254G.A 386G.A 1 IL17 unknown 3 3 E60X c.178G.T 310G.T 0 IL17 x 3 3 L88IfsX22 c.262_263delTT 394delTT 0 IL17 x 4 4 E92K 21.92 c.274G.A 406G.A 2 CFMDB c.164+1G.A; c.2051- 2AA.G 4 4 L101X c.302T.G 434T.G 1 CFMDB c.3717+12191C.T 4 4 K114IfsX5 c.341_353del13bp 473del13bp 1 Novel F508del 4 4 R117H 20.35 c.350G.A 482G.A 5 IL17 F508del; 2x unknown 4 4 R117C 22.07 c.349C.T 481C.T 2 CFMDB S1206X;1x unknown 4 4 L137_L138insT c.412_413insACT L138ins 1 CFMDB F508del 4 4 R153I 22.61 c.458G.T 590G.T 2 Novel F508del; c.3527delC i4 i4 IVS4_Donor c.489+1G.T 621+1G.T 5 IL17 F508del; c.489+1G.T 5 5 L165X c.494T.A 626T.A 1 Novel F508del i5 i5 IVS5_Donor c.579+1G.T 711+1G.T 0 IL19 x i5 i5 IVS5_Donor c.579+3A.G 711+3A.G 2 CFMDB 2,3del21kb; c.2052-3insA i5 i5 IVS5_Donor c.579+5G.A 711+5G.A 0 IL17 x 7 8 F311L 20.90 c.933C.G 965C.G 2 CFMDB 2x F508 7 8 G314R 20.58 c.940G.A 1072G.A 4 CFMDB various CF mutations 7 8 F316LfsX12 c.948delT 1078delT 1 IL17 unkown 7 8 R334W 22.41 c.1000C.T 1132C.T 6 IL17 various CF mutations 7 8 I336K 22.07 c.1007T.A 1139T.A 2 CFMDB 2,3de21kb; F508del 7 8 R347P 22.27 c.1040G.C 1172G.C 11 IL17 various CF mutations i7 i8 IVS8_Donor c.1116+2T.A 1248+2T.A 1 Novel Q1412X 9 10 A455E 22.61 c.1364C.A 1496C.A 0 IL17 x i9 i10 IVS10_Donor c.1392+1G.A 1524+1G.A 1 CFMDB c.3816-7delGT 10 11 S466X c.1397C.G 1529C.G 1 CFMDB G542X 10 11 I507del c.1519_1521delATC 1651delATC 2 IL19 F508del 10 11 F508del c.1521_1523delCTT 1654delCTT 805 IL19 various CF mutations i10 i11 IVS11_Acceptor c.1585-1G.A 1717-1G.A 27 IL19 various CF mutations 11 12 G542X c.1624G.T 1756G.T 25 IL19 various CF mutations 11 12 G551D 21.24 c.1624G.T 1756G.T 5 IL19 various CF mutations 11 12 Q552X c.1654C.T 1786C.T 0 IL19 x 11 12 R553X c.1657C.T 1789C.T 14 IL19 various CF mutations 11 12 R560T 21.92 c.1679G.C 1811G.C 0 IL19 x i12 i13 IVS13_Donor c.1766+1G.A 1898+1G.A 6 IL19 various CF mutations i12 i13 IVS13_Donor c.1766+1G.C 1898+1G.C 1 CFMDB F508del 13 14 H620P 21.73 c.1859A.C 1991A.C 1 CFMDB F508del 13 14 R668C//G576A 21.61//1.73 c.2002C.T//c.1727G.C 2134C.T// 1859G.C 5 b CFMDB// rs1800098 c.1585-1G.A; 4 unknown 13 14 L671X c.2012delT 2143delT 27 IL17 various CF mutations 13 14 K684SfsX38 c.2051_2052delAAinsG 2183AA.G 10 IL17 various CF mutations 13 14 K684NfsX38 c.2052delA 2184delA 0 IL17 x 13 14 Q685TfsX4 c.2052_2053insA 2184insA 15 CFMDB various CF mutationsc , 1 unknown Table 2. Cont. Exon / intron (legacy) Exon / intron (Ensembl) Protein change SVM value cDNA (HGVS nomenclature) gDNA (cDNA +132 bp) Number of PL CF chromosomes Reference a Mutations in trans 13 14 L732X c.2195T.G 2327T.G 1 CFMDB F508del 14A 15 R851X c.2551C.T 2683C.T 3 CFMDB various CF mutations 14A 15 I864SfsX28 c.2589_2599del11bp 2721del11bp 2 CFMDB F508del; 2,3del21kb i14B i16 IVS16_Donor c.2657+2_2657+3insA 2789+2insA 1 CFMDB F508del i14B i16 IVS16_Donor c.2657+5G.A 2789+5G.A 0 IL17 unkown 15 17 Y919C 21.02 c.2756A.G 2888A.G 1 CFMDB unknown 15 17 H939HfsX27 c.2817_2820delTACTC 2949delTACTC 1 Novel unkown i15 i17 IVS17_Donor c.2908+3A.C 3040+3A.C 1 Novel F508del i16 i18 IVS18_Donor c.2988+1G.A 3120+1G.A 0 IL19 x 17A 19 I1023_V1024del c.3067_3072delATAGTG 3199del6 0 IL19 x i17A i19 IVS19 c.3140-26A.G 3272-26A.G 9 IL19 various CF mutations 17B 20 L1065R 21.90 c.3194T.G 3326T.G 1 CFMDB F508del 17B 20 Y1092X c.3276C.A 3408C.A 1 CFMDB R334W i18 i21 IVS21_Donor c.3468+2_3468+3insT 3600+2insT 11 CFMDB various CF mutationsd , 1 unknown 18 21 E1126EfsX7 c.3376_3379delGAAG 3508delGAAG 1 Novel F508del 19 22 R1158X c.3472C.T 3604C.T 2 CFMDB F508del; R553X 19 22 R1162X c.3484C.T 3616C.T 1 IL17 F508del 19 22 L1177SfsX15 c.3528delC 3659delC 4 IL17 various CF mutations 19 22 S1206X c.3617C.A 3749C.A 1 CFMDB R117C i19 i22 IVS22 c.3717+12191C.T 3849+10kbC.T 58 IL17 various CF mutations 20 23 G1244R 22.62 c.3730G.C 3862G.C 1 CFMDB F508del 20 23 S1251N 22.28 c.3752G.A 3884G.A 0 IL19 x 20 23 L1258FfsX7 c.3773_3774insT 3905insT 0 IL19 x 20 23 V1272VfsX28 c.3816_3817delGT 3944delGT 1 CFMDB c.1392+1G.A 20 23 W1282X c.3846G.A 3978G.A 9 IL19 various CF mutations 21 24 N1303K 22.62 c.3909C.G 4041C.G 18 IL19 various CF mutations 22 25 V1327X c.3979delG 4111delG 1 Novel F508del 22 25 S1347PfsX13 c.4035_4038dupCCTA c.4167dupCCTA 1 CFMDB 2,3del21kb 23 26 Q1382X c.4144C.T 4276C.T 1 CFMDB F508del 23 26 Q1412X c.4234C.T 4366C.T 2 CFMDB F508del; c.1116+2T.A i23 i26 IVS26_Donor c.4242+1G.T 4374+1G.T 1 CFMDB F508del Sequence changes of uncertain pathogenic effect, tentatively counted as mutations 6A 6 E217G 0.30 c.650A.G 782A.G 1 CFMDB; rs1219109046 unknown 7 8 R352Q 20.01 c.1055G.A 1187G.A 1 CFMDB; rs121908753 F508del 7 8 Q359R 0.33 c.1076A.G 1208A.G 1 CFMDB F508del i8 i9 IVS9 c.1210-12T5_1210- 34_35 (TG)12 1332-12Tn_- 34TGm 6 CFMDB F508del; 3x unknown i8 i9 IVS9 c.1210-12T5_1210- 34_35 (TG)13 1332-12Tn_- 34TGm 2 CFMDB 2143delT; 1x unknown i8 i9 IVS9 c.1210-12T8 1332-12Tn 1 Novel unknown 10 11 I506V 20.21 c.1516A.G 1648A.G 1 CFMDB; rs1800091 unknown 12 13 V562L 0.79 c.1684G.C 1816G.C 1 CFMDB; rs1800097 unknown 13 14 G723V 0.44 c.2168G.T 2300G.T 1 CFMDB; rs200531709 unknown 15 17 D924N 0.03 c.2770G.A 2902G.A 1 CFMDB; rs201759207 unknown patient with F508del on another allele) was not supported by the SVM value (+0.35); the patient was PS and had ambiguous chloride values (45, 64 and 83 mmol/L).
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ABCC7 p.Gln1412* 24586523:71:1638
status: NEWX
ABCC7 p.Gln1412* 24586523:71:4736
status: NEW154 Table 4. Cont. Mutations a Poland Czechs Slovakia c Germany Lithuania W. Ukraine E. Hungary Romania c Bulgaria Serbia Greece Number of chromosomes 1476 1200 856 700 98 264 80 256 208 352 874 F311L 0.14 0 NA 0 0 0 0 NA 0 0 0 Q1412X 0.14 0 NA 0 0 0 0 NA 0 0 0 Other reported 1.52 8.51 NA 7.10 2.0 1.14 7.50 3.8 12,03 4.28 17.83 Not detected 17.5 0.50 13.89 4.57 35.8 16.29 6.25 27.7 8.17 17.43 9.15 Estimated efficiency of INNOLiPA tests 75.5 89.9 84.0 88.7 61.2 74.6 87.5 69.1 80.3 78.7 73.3 Legend: Data are given in %.
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ABCC7 p.Gln1412* 24586523:154:224
status: NEW[hide] Understanding how cystic fibrosis mutations disrup... Int J Biochem Cell Biol. 2014 Jul;52:47-57. doi: 10.1016/j.biocel.2014.04.001. Epub 2014 Apr 13. Wang Y, Wrennall JA, Cai Z, Li H, Sheppard DN
Understanding how cystic fibrosis mutations disrupt CFTR function: from single molecules to animal models.
Int J Biochem Cell Biol. 2014 Jul;52:47-57. doi: 10.1016/j.biocel.2014.04.001. Epub 2014 Apr 13., [PMID:24727426]
Abstract [show]
Defective epithelial ion transport is the hallmark of the life-limiting genetic disease cystic fibrosis (CF). This abnormality is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), the ATP-binding cassette transporter that functions as a ligand-gated anion channel. Since the identification of the CFTR gene, almost 2000 disease-causing mutations associated with a spectrum of clinical phenotypes have been reported, but the majority remain poorly characterised. Studies of a small number of mutations including the most common, F508del-CFTR, have identified six general mechanisms of CFTR dysfunction. Here, we review selectively progress to understand how CF mutations disrupt CFTR processing, stability and function. We explore CFTR structure and function to explain the molecular mechanisms of CFTR dysfunction and highlight new knowledge of disease pathophysiology emerging from large animal models of CF. Understanding CFTR dysfunction is crucial to the development of transformational therapies for CF patients.
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No. Sentence Comment
2033 For example, the CF-PI mutation Q1412X, which truncates the last 70 amino acids of CFTR, generated macroscopic cAMP-stimulated Cl-currents with similar biophysical properties, but reduced magnitude compared to wild-type CFTR (Haardt et al., 1999).
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ABCC7 p.Gln1412* 24727426:2033:32
status: NEW2034 Biochemical studies demonstrated that Q1412X was without effect on CFTR processing and intracellular transport, but greatly reduced the stability of mature CFTR protein (half-life in COS cells: wild-type CFTR, 14 h; Q1412X, 3.5 h).
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ABCC7 p.Gln1412* 24727426:2034:38
status: NEWX
ABCC7 p.Gln1412* 24727426:2034:216
status: NEW[hide] [Challenges of personalized medicine for cystic fi... Arch Pediatr. 2015 Jul;22(7):778-86. doi: 10.1016/j.arcped.2015.04.015. Epub 2015 May 26. Corvol H, Taytard J, Tabary O, Le Rouzic P, Guillot L, Clement A
[Challenges of personalized medicine for cystic fibrosis].
Arch Pediatr. 2015 Jul;22(7):778-86. doi: 10.1016/j.arcped.2015.04.015. Epub 2015 May 26., [PMID:26021452]
Abstract [show]
Personalized medicine, or P4 medicine for "Personalized", "Predictive", "Preventive" and "Participatory", is currently booming for cystic fibrosis, with the development of therapies targeting specific CFTR mutations. The various challenges of personalized medicine applied to cystic fibrosis issues are discussed in this paper.
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No. Sentence Comment
56 Ce sont principalement des mutations ge &#b4;ne &#b4;rant des prote &#b4;ines tronque &#b4;es dans leur partie C-terminale comme Q1412X et 4326delTC.
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ABCC7 p.Gln1412* 26021452:56:129
status: NEW