ABCMdb

ABCC7 p.Thr164Ile

CF databases:	c.490A>G , p.Thr164Ala (CFTR1) ? ,
Predicted by SNAP2:	A: N (82%), C: D (53%), D: D (75%), E: D (80%), F: D (75%), G: D (66%), H: D (71%), I: N (78%), K: D (80%), L: N (61%), M: D (63%), N: D (63%), P: D (75%), Q: D (71%), R: D (80%), S: N (57%), V: N (78%), W: D (85%), Y: D (59%),
Predicted by PROVEAN:	A: N, C: N, D: D, E: N, F: D, G: N, H: D, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, V: N, W: D, Y: D,

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[hide] beta2 adrenoceptor gene polymorphisms in cystic fi... Pharmacogenetics. 2002 Jul;12(5):347-53. Buscher R, Eilmes KJ, Grasemann H, Torres B, Knauer N, Sroka K, Insel PA, Ratjen F
beta2 adrenoceptor gene polymorphisms in cystic fibrosis lung disease.
Pharmacogenetics. 2002 Jul;12(5):347-53., [PMID:12142724]

Abstract [show]
The cystic fibrosis membrane conductance regulator can be activated through beta2-adrenoceptor (beta2AR) stimulation. We tested the hypothesis that coding sequence polymorphisms in the beta2AR gene contribute to the disease state in patients with cystic fibrosis. The Arg16Gly, Gln27Glu, and Thr164Ile beta2AR polymorphisms were studied by specific polymerase chain reaction and restriction fragment length polymorphism analysis in 126 cystic fibrosis patients. Forced expiratory volume in 1 s was significantly (P < 0.05) reduced in cystic fibrosis patients carrying the Gly16 allele in either homozygous or heterozygous form (Gly16Gly + Arg16Gly) compared to patients homozygous for the Arg16 allele (60.3 +/- 3.5% versus 75.7 +/- 4.9% predicted). Similarly, forced vital capacity and flows at lower lung volumes were significantly (P < 0.05 and P < 0.01) lower in cystic fibrosis patients carrying the Gly16 allele. In addition, the Gly16 allele was associated with a greater 5 year decline in pulmonary function (P < 0.01). Bronchodilator responses to albuterol were not significantly different between the groups. The Thr164Ile variant was found in four patients; these patients had markedly reduced pulmonary function. Isoproterenol-stimulated cyclic AMP formation was significantly blunted in cystic fibrosis patients carrying either the Gly16 allele or Thr164Ile genotype compared to cystic fibrosis patients homozygous for the respective Arg16 alleles. These data provide the first evidence suggesting that polymorphisms of the beta2AR gene contribute to clinical severity and disease progression in cystic fibrosis.

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18 Nine different polymorphic loci in the â2AR gene have been identified, of which four change the amino acid sequence of the â2AR protein: Arg16 Gly, Gln27 Glu, Val34 Met and Thr164 Ile [12]. Login to comment
20 The only genetic variant that leads to a decreased binding of agonist is the Thr164 Ile polymorphism which is rare (, 5%) and has been found only in heterozygous form [12]. Login to comment
32 Subjects were analysed according to their genotype for the Arg16 Gly, Gln27 Glu and Thr164 Ile alleles. Login to comment
33 Patients with the genotype Arg16 Arg, Gln27 Gln and Thr164 Thr carry the wild-type alleles, Arg16 Gly, Gln27 Glu and Thr164 Ile are heterozygous for the alleles and individuals with the Gly16 Gly or Glu27 Glu genotype are homozygous for the respective polymorphic allele. Login to comment
45 The primers used for detection of the Thr164 Ile polymorphism were forward primer (59- GTGATCGCAGTGGATCGCTACT-39) and reverse primer (59-AGAGCAAGACCATGATCACCAG-39), and an annealing temperature of 58 8C was used. Login to comment
76 The frequency of the Thr164 Ile polymorphism is below 5% within different populations [10,11,14] and, in our study, was only detected in four cystic fibrosis patients in heterozygous form. Login to comment
83 Isoproterenol-stimulated cAMP formation, expressed as percentage of basal stimulation, was significantly decreased in patients heterozygous for the Thr164 Ile polymorphism compared to four subjects homozygous for Arg16 , Gln27 and Thr164 (P ¼ 0.0013) (Fig. 3). Login to comment
84 cAMP formation in subjects double-heterozygous for Arg16 Gly and Gln27 Glu was similar to that of subjects who had the Thr164 Ile polymorphism (Fig. 3). Login to comment
104 Similarly, patients homozygous for the Thr164 allele have significantly higher values for FVC, FEV1 and MEF50 when compared to heterozygous allele carriers (Thr164 Ile). Login to comment
105 100 50 0 %predicted FVC FEV1 MEF50% Thr164Thr Thr164Ile * * * 100 75 50 -4 -3 -2 -1 0 Time (year) FEV1(%predicted) * Arg16Arg n ϭ 22 Arg16 Gly ϩ Gly16 Gly n ϭ 37 Fig. 2 Evolution of pulmonary function, expressed as decline in FEV1 in percentage predicted, over 5 years in 59 cystic fibrosis patients. Login to comment
107 1000 500 0 -10 -9 -8 -7 -6 -log[iso] cAMPformation (%ofbasal) CF Thr164 Ile CF Arg16 Arg ϩ CF Gln27 Gln ϩ CF Thr164 Thr CF Arg16 Gly ϩ CF Gln27 Glu ϩ CF Thr164 Thr n ϭ 3 n ϭ 4 n ϭ 4 * Fig. 3 Isoproterenol-induced cyclic AMP formation in four cystic fibrosis patients, each of whom were either heterozygous for Thr164 Ile (j), homozygous for Thr164 , Arg16 and Gln27 (m), or heterozygous for Arg16 Gly and Gln27 Glu but homozygous for Thr164 (.). Login to comment

[hide] Long-acting bronchodilators in cystic fibrosis. Curr Opin Pulm Med. 2003 Nov;9(6):504-8. Colombo JL
Long-acting bronchodilators in cystic fibrosis.
Curr Opin Pulm Med. 2003 Nov;9(6):504-8., [PMID:14534403]

Abstract [show]
PURPOSE OF REVIEW: Over 80% of patients with cystic fibrosis (CF) have bronchodilator therapy prescribed, yet bronchodilator use in CF remains controversial. The development of long-acting beta-agonist drugs for clinical use has provided additional rationale for considering bronchodilator therapy in CF. This paper will review recent developments in bronchodilator use in CF patients, with emphasis on the long-acting beta agonists. RECENT FINDINGS: It is reported that 50 to 60% of CF patients demonstrate significant intermittent airway hyperreactivity in response to bronchodilators or challenges. The beta-agonist drugs are the most commonly prescribed bronchodilators. Several mechanisms may be implicated in therapeutic response of CF patients to bronchodilators including direct smooth muscle relaxation, increased mucociliary clearance, direct effects on inflammatory cells and bacterial adherence, and possible direct effects on CF transmembrane conductance regulator (CFTR) function. Several recent studies have shown improved outcomes with long-acting bronchodilators. SUMMARY: In spite of the widespread use of bronchodilators, there are very few long-term studies of their effects in CF patients. However, there are clearly clinical benefits in certain situations. Further research into the most appropriate utilization of these medications to improve outcomes in patients with CF would be helpful.

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114 CF patients with Gly16 allele or Thr164Ile genotypes had significantly worse lung function compared to those homozygous for the Arg16 allele. Login to comment

[hide] Lung disease modifier genes in cystic fibrosis. Int J Biochem Cell Biol. 2014 Jul;52:83-93. doi: 10.1016/j.biocel.2014.02.011. Epub 2014 Feb 22. Guillot L, Beucher J, Tabary O, Le Rouzic P, Clement A, Corvol H
Lung disease modifier genes in cystic fibrosis.
Int J Biochem Cell Biol. 2014 Jul;52:83-93. doi: 10.1016/j.biocel.2014.02.011. Epub 2014 Feb 22., [PMID:24569122]

Abstract [show]
Cystic fibrosis (CF) is recognized as a single gene disorder. However, a considerable diversity in its clinical phenotype has been documented since the description of the disease. Identification of additional gene alleles, so called "modifier genes" that directly influence the phenotype of CF disease became a challenge in the late '90ies, not only for the insight it provides into the CF pathophysiology, but also for the development of new potential therapeutic targets. One of the most studied phenotype has been the lung disease severity as lung dysfunction is the major cause of morbidity and mortality in CF. This review details the results of two main genetic approaches that have mainly been explored so far: (1) an "a priori" approach, i.e. the candidate gene approach; (2) a "without a priori" approach, analyzing the whole genome by linkage and genome-wide association studies (GWAS), or the whole exome by exome sequencing.

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2274 Several of these SNPs alter the protein structure by causing a change in amino acid: Arg16Gly, Arg19Cys, Glu27Gln, Val34Met, and Thr164Ile (Hall, 2006). Login to comment