ABCMdb

ABCC7 p.Glu264Val

Predicted by SNAP2:	A: D (80%), C: D (80%), D: D (85%), F: D (91%), G: D (91%), H: D (91%), I: D (91%), K: D (91%), L: D (91%), M: D (85%), N: D (85%), P: D (91%), Q: D (80%), R: D (91%), S: D (71%), T: D (85%), V: D (85%), W: D (91%), Y: D (91%),
Predicted by PROVEAN:	A: D, C: D, D: N, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: N, R: D, S: D, T: D, V: D, W: D, Y: D,

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[hide] Genetics of chronic pancreatitis. J Pediatr Gastroenterol Nutr. 2002 Feb;34(2):125-36. Witt H, Becker M
Genetics of chronic pancreatitis.
J Pediatr Gastroenterol Nutr. 2002 Feb;34(2):125-36., [PMID:11840029]

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246 There are two frequent genetic defects in the gene that lead to an ␣1-antitrypsin deficiency: a glutamine-to-valine substitution at codon 264 in exon 5 (E264V) (PiS) and a glutamine to lysine substitution at codon 342 in exon 7 (E342K) (PiZ) (91). Login to comment

[hide] Relevance of variants in serum antiproteinases for... Scand J Gastroenterol. 2002 Mar;37(3):360-5. Teich N, Walther K, Bodeker H, Mossner J, Keim V
Relevance of variants in serum antiproteinases for the course of chronic pancreatitis.
Scand J Gastroenterol. 2002 Mar;37(3):360-5., [PMID:11916201]

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BACKGROUND: Mutations of the pancreatic serine protease inhibitor, Kazal type 1 (SPINK1), the cationic trypsinogen (PRSS1) and the cystic fibrosis transmembrane conductance regulator (CFTR) were reported to be genetic risk factors of chronic pancreatitis (CP). The aim of this study was to determine the role of genetic variants of the main serum antiproteinases alpha-1-antitrypsin (AAT) and alpha-2-macroglobulin (A2M) for the course of chronic pancreatitis. METHODS: 124 patients with non-alcoholic chronic pancreatitis (with PRSS1 or SPINK1 mutations or idiopathic pancreatitis) and 64 healthy controls were investigated for the AAT mutations PiS and PiZ, and the PiM determining variants R101H, V213A, E376D. In 101 subjects, the 'bait region' of A2M was sequenced. A pentanucleotide deletion in the bait region of A2M was analysed in 147 chronic pancreatitis (CP) patients and 87 controls. RESULTS: The lowest prevalences of V213A and E376D were found in PRSS1 patients, whereas an increased rate of these mutations was present in the SPINK1 group, and the highest prevalence was found in patients with idiopathic pancreatitis. The prevalence of PiM variants was higher in patients with early onset CP than in late onset (P < 0.05 for E376D). The coding region of the bait region of A2M was of wild type in all investigated subjects. The A2M pentanucleotide deletion showed a homogenous distribution in patients and controls. CONCLUSIONS: Our study suggests a moderating, but not predominant, role of AAT variants in the course of chronic non-alcoholic pancreatitis.

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47 The E264V mutation in exon 3, resulting in the PiS mutation, was investigated using a mutation speci c PCR approach. Login to comment
80 Distribution of AAT variants in patients with chronic pancreatitis of different genetic background and controls Chronic pancreatitis Controls All PRSS1 SPINK1 IP 64 124 21 54 49 Age Median 29 19 35 25 12 Range 18-53 2-78 2-78 8-64 4-23 AAT variant R101H 30% 36% 38% 30% 41% ^19, *0 ^43, *1 ^8, *0 ^15, *1 ^20, *0 V213A 44% 43% 23% 43% 51% ^24, *4 ^40, *13 ^4, *1 ^17, *6 ^19, *6 E264V 3% 4% 10% 4% 2% ^2, *0 ^5, *0 ^2, *0 ^2, *0 ^1, *0 E342K 5% 2% 0% 0% 4% ^2, *1 ^2, *0 ^0, *0 ^0, *0 ^2, *0 E376D 39% 43% 33% 39% 51% ^24, *1 ^43, *10 ^5, *2 ^15, *6 ^23, *2 No 23% 19% 29% 20% 14% ^ Heterozygous, * homozygous. Login to comment

[hide] Chronic pancreatitis and cystic fibrosis. Gut. 2003 May;52 Suppl 2:ii31-41. Witt H
Chronic pancreatitis and cystic fibrosis.
Gut. 2003 May;52 Suppl 2:ii31-41., [PMID:12651880]

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Recent discoveries of trypsinogen and trypsin inhibitor mutations in patients with chronic pancreatitis (CP) support the hypothesis that an inappropriate activation of pancreatic zymogens to active enzymes within the pancreatic parenchyma starts the inflammatory process. Current data suggest that CP may be inherited dominant, recessive, or complex as a result of mutations in the above mentioned or yet unidentified genes. Evaluation of patients with CP should include genetic testing. Cystic fibrosis (CF) is an autosomal recessive inherited disorder caused by mutations in the CF transmembrane conductance regulator (CFTR) gene and is characterised by pancreatic insufficiency and chronic bronchopulmonary infection. The progression and severity of pulmonary disease differs considerably between people with identical CFTR mutations and does not seem to correlate with the type or class of the CFTR mutation. The identification of further disease modifying genetic factors will increase the pathophysiological understanding and may help to identify new therapeutic targets.

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338 Two frequent genetic defects lead to an α1 antitrypsin deficiency: a glutamine to valine substitution at codon 264 (E264V) (PiS) and a glutamine to lysine substitution at codon 342 (E342K) (PiZ).53 An association between α1 antitrypsin deficiency and CP has been suggested by several case reports and two systematic studies,54 55 but conflicting results were obtained by other authors.56-58 All these studies, however, were performed by either α1 antitrypsin phenotyping or by measurement of serum concentrations and focused predominantly on alcohol induced pancreatitis. Login to comment

[hide] Analysis of CFTR, SPINK1, PRSS1 and AAT mutations ... J Pediatr Gastroenterol Nutr. 2006 Sep;43(3):299-306. Sobczynska-Tomaszewska A, Bak D, Oralewska B, Oracz G, Norek A, Czerska K, Mazurczak T, Teisseyre M, Socha J, Zagulski M, Bal J
Analysis of CFTR, SPINK1, PRSS1 and AAT mutations in children with acute or chronic pancreatitis.
J Pediatr Gastroenterol Nutr. 2006 Sep;43(3):299-306., [PMID:16954950]

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OBJECTIVES: Defects of PRSS1, SPINK1, CFTR and AAT are considered causative or predisposing to pancreatitis. The aim of this study was to evaluate the impact of these defects into molecular pathology of chronic pancreatitis (CP) and acute recurrent pancreatitis (ARP). METHODS: Ninety-two children with CP or ARP, 55 family members and 50 controls were investigated. The subjects were screened for PRSS1 mutations: R122H, R122C, A16V, N29I; SPINK1 N34S variant; panel of 14 CFTR defects: INNOLiPA CFTR12, CFTRdele2,3 and IVS8-T variant or panel of 3 CFTR defects-F508del, CFTRdele2,3 and IVS8-T; AAT mutations: E264V, E342K. RESULTS: We identified 1 mutated allele in at least 1 of 4 genes in 31 of 92 patients and 12 of 50 controls (P = 0.157). Mutations in SPINK1 and PRSS1 were most frequent. PRSS1 mutations were identified mainly in CP patients (9.6% of CP vs 2.5% of ARP alleles, P = 0.094), whereas N34S SPINK1 mutation was present with comparable frequency in CP and ARP patients (7.7% vs 10.0%, P = 0.768). The frequency of mutations in CFTR alleles was similar to controls (4.9% vs 5%, P = 0.587). Overall frequency of AAT mutations was lower than in the controls. Family studies showed that defects in the examined genes did not always segregate with disease. CONCLUSIONS: PRSS1 defects seem to be causative for pancreatitis, whereas defects in SPINK1 are suggested to be associated with the disease. No association between CFTR mutations and pancreatitis was observed. The importance of AAT variants remains speculative.

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3 The subjects were screened for PRSS1 mutations: R122H, R122C, A16V, N29I; SPINK1 N34S variant; panel of 14 CFTR defects: INNOLiPA CFTR12, CFTRdele2,3 and IVS8-T variant or panel of 3 CFTR defectsVF508del, CFTRdele2,3 and IVS8-T; AAT mutations: E264V, E342K. Login to comment
63 Genotyping for E264V (PiS) and E342K (PiZ) variants of AAT was done in accordance with Henry et al. (15). Login to comment
74 Molecular defects were found in 12 control samples: 5 cases of IVS8-5T/j (CFTR), 2 cases of N34S/j (SPINK1) and 5 cases of the E264V: 1 x E264V/E264V, 4 x E264V/j (AAT). Login to comment
90 In contrast, the overall frequency of mutations E264V and E342K in the AAT was lower than in the control group (Table 3). Login to comment
143 In our study, the frequency of the PIS (E264V) and PIZ (E342K) alleles was lower than for control group (Table 3). Login to comment

[hide] Update on gene modifiers in cystic fibrosis. Curr Opin Pulm Med. 2008 Nov;14(6):559-66. Collaco JM, Cutting GR
Update on gene modifiers in cystic fibrosis.
Curr Opin Pulm Med. 2008 Nov;14(6):559-66., [PMID:18812833]

Abstract [show]
PURPOSE OF REVIEW: Cystic fibrosis (CF) is a common, life-limiting monogenic disease, which typically manifests as progressive bronchiectasis, exocrine pancreatic dysfunction, and recurrent sinopulmonary infections. Although the gene responsible for CF (CFTR) was described in 1989, it has become increasingly evident that modifier genes and environmental factors play substantial roles in determining the severity of disease, particularly lung disease. Identifying these factors is crucial in devising therapies and other interventions to decrease the morbidity and mortality associated with this disorder. RECENT FINDINGS: Although many genes have been proposed as potential modifiers of CF, only a handful have withstood the test of replication. Several of the replicated findings reveal that genes affecting inflammation and infection response play a key role in modifying CF lung disease severity. Interactions between CFTR genotype, modifier genes, and environmental factors have been documented to influence lung function measures and infection status in CF patients. SUMMARY: Several genes have been demonstrated to affect disease severity in CF. Furthermore, it is likely that gene-gene and gene-environment interactions can explain a substantial portion of the variation of lung disease. Ongoing genome-wide studies are likely to identify novel genetic modifiers. Continued exploration of the role of genetic and nongenetic modifiers of CF is likely to yield new options for combating this debilitating disease.

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80 Three commonly studied mutations include the S mutation in exon 3 (Glu264Val or c2313T>A) and the Z mutation in exon 5 (Glu342Lys or c4627G>A), which result in reduced plasma levels of a1-antitrypsin, and þ1237G>A in the 30 -untranslated region, which may result in a decrease in acute phase levels [60]. Login to comment

[hide] An MBL2 haplotype and ABCB4 variants modulate the ... Dig Liver Dis. 2009 Nov;41(11):817-22. Epub 2009 May 20. Tomaiuolo R, Degiorgio D, Coviello DA, Baccarelli A, Elce A, Raia V, Motta V, Seia M, Castaldo G, Colombo C
An MBL2 haplotype and ABCB4 variants modulate the risk of liver disease in cystic fibrosis patients: a multicentre study.
Dig Liver Dis. 2009 Nov;41(11):817-22. Epub 2009 May 20., [PMID:19467940]

Abstract [show]
BACKGROUND: Cystic fibrosis is the most common lethal recessive disorder among Caucasians. Over 1500 mutations have been identified in cystic fibrosis transmembrane conductance regulator disease-gene so far. A large variability of the clinical phenotype has been observed both in cystic fibrosis patients bearing the same genotype, and in affected sibpairs. Thus, genes inherited independently from cystic fibrosis transmembrane conductance regulator could modulate the clinical expression of cystic fibrosis. METHODS: We analysed some putative modifier genes of liver cystic fibrosis phenotype (serpin 1, hemochromatosis, transferrin receptor 2, ferroportin 1, mannose binding lectin and adenosine triphospate-binding cassette subfamily B member 4) in 108 unrelated cystic fibrosis patients with and without liver involvement. RESULTS: HYPD mannose binding lectin haplotype was significantly (p<0.05) more frequent in cystic fibrosis patients with liver disease versus those without liver disease. This haplotype already related to a more severe pulmonary cystic fibrosis phenotype, is associated to a reduced MBL immunological activity. The c.834-66G>T variant of adenosine triphospate-binding cassette subfamily B member 4 gene was significantly (p<0.05) less frequent in cystic fibrosis patients with liver disease as compared to those with no liver disease. CONCLUSIONS: The HYPD mannose binding lectin haplotype may predispose a subgroup of cystic fibrosis patients to a more severe liver involvement impairing the local defence mechanisms whereas the c.834-66G>T adenosine triphospate-binding cassette subfamily B member 4 variant may enhance the activity of the protein and thus exert a protective effect toward liver disease.

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64 Gene variants CF patients genotypes CF patients alleles With liver disease Without liver disease Fisher p-value With liver disease Withoutliver disease Fisher p-value W.T. het homo W.T. het homo Allele 1 Allele 2 Allele 1 Allele 2 HFE p.H63D 48 14 0 30 14 2 0.14 110 14 74 18 0.12 p.S65C 61 1 0 44 2 0 0.57 123 1 90 2 0.58 p.C282Y 62 0 0 44 2 0 0.18 124 0 90 2 0.18 SPE p.R101H 41 19 0 24 22 0 0.11 101 19 70 22 0.16 p.V213A 45 14 1 28 16 2 0.26 104 16 72 20 0.14 p.D256D 59 1 0 46 0 0 1.00 119 1 92 0 1.00 p.E264V 60 0 0 44 2 0 0.18 120 0 90 2 0.19 p.E376D 40 17 3 30 15 1 0.77 97 23 75 17 1.00 ABCB4 c.287-61C>T 56 0 0 40 6 0 0.52 112 0 86 6 0.54 c.351A>T 31 1 0 45 1 0 1.00 63 1 91 1 1.00 c.504T>C 17 38 6 17 17 12 0.017 72 50 51 41 0.68 c.523A>G 59 2 0 46 0 0 0.50 120 2 92 0 0.51 c.711A>T 47 13 1 27 18 1 0.08 107 15 72 20 0.09 c.834-66G>T 48 13 0 27 18 1 0.04 109 13 72 20 0.03 c.1005+7A>C 60 1 0 46 0 0 1.00 121 1 92 0 1.00 c.1005+41T>G 60 1 0 46 0 0 1.00 121 1 92 0 1.00 c.1357-40G>A 53 7 1 38 8 0 0.57 113 9 84 8 0.80 c.1529A>G 61 0 0 45 1 0 0.43 122 0 91 1 0.43 c.1732-39A>G 54 0 0 36 1 0 0.41 108 0 73 1 0.41 c.1893+34G>C 53 1 0 37 0 0 1.00 107 1 74 0 1.00 c.1954A>G 48 13 0 41 5 0 0.20 109 13 87 5 0.22 c.2064+55A>G 48 13 0 41 5 0 0.20 109 13 87 5 0.22 c.2211+16T>C 53 7 1 39 7 0 0.87 113 9 85 7 1.00 c.2478+40A>G 49 11 0 40 5 0 0.41 109 11 85 5 0.43 c.2479-67delG 49 12 0 38 5 0 0.42 110 12 81 5 0.44 c.2555A>G 61 1 0 45 1 0 0.43 123 1 91 1 0.43 c.3508-88T>C 61 1 0 45 1 0 0.43 123 1 91 1 0.43 c.3508-16C>T 52 7 1 37 9 0 0.34 111 9 83 9 0.62 c.3655-72T>C 49 12 0 40 5 0 0.29 110 12 85 5 0.31 wt: wild type; het: heterozygotes; homo: homozygotes; significantly different results are reported in bold. Login to comment
98 Similarly, we did not find differences in the frequency of the p.E264V mutation of SPE gene between CF patients with and without liver disease; furthermore, none of the subjects of our study had the other SPE mutation (i.e., p.E342K) that together to p.E264V causes the A1AT deficient phenotype [37]. Login to comment