ABCMdb

PMID: 10950058

Ockenga J, Stuhrmann M, Ballmann M, Teich N, Keim V, Dork T, Manns MP
Mutations of the cystic fibrosis gene, but not cationic trypsinogen gene, are associated with recurrent or chronic idiopathic pancreatitis.
Am J Gastroenterol. 2000 Aug;95(8):2061-7., [PubMed]

Sentences

No. Mutations Sentence Comment

8 ABCC7 p.Tyr1092* ABCC7 p.Ile336Lys Three patients (15.0%) had a cystic fibrosis (CF) mutation on one chromosome (⌬F508, I336K, Y1092X), which is known to cause phenotypical severe cystic fibrosis. Login to comment 10 ABCC7 p.Arg75Gln ABCC7 p.Arg75Gln ABCC7 p.Ile336Lys In addition, two possibly predisposing CFTR variants (R75Q, 1716G3A) were detected on four patients, one of these being a compound heterozygous for the missense mutation I336K and R75Q. Login to comment 11 ABCC7 p.Arg75Gln ABCC7 p.Ile336Lys No other family member (maternal I336K; paternal R75Q; sister I1336K) developed pancreatitis. Login to comment 28 ABCC7 p.Arg117His To date, five mutations with varying effect on the developing of the disease have been identified (R117H, N21I, K23R, A16V, D22G (8-12). Login to comment 53 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Ser1251Asn ABCC7 p.Glu60* Using the ARMS technology (elucigene CF20, Zeneca Diagnostics, Oxfordshire, UK) all samples were tested additionally for the mutations E60X, R347P, A455E, 1078delT, 2183AA3G, G542X, G551D, N1303K, W1282X, 1717-1G3A, R553X, 621ϩ1G3T, R117H, R1162X, 3849ϩ10kbC3T, R334W, S1251N, and 3659delC. Login to comment 54 ABCC7 p.Arg347His ABCC7 p.Arg75Gln ABCC7 p.Tyr1092* ABCC7 p.Asp1152His ABCC7 p.Ile336Lys Finally, we tested all samples for the presence of mutations or variants R75Q, I336K, R347H, IVS8-5T (5T allele), 1716G3A, 2143delT, 2789ϩ5G3A, Y1092X, 3272-26A3G, D1152H, and CFTRdel2,3 (21kb) by PCR and restriction enzyme digestion with the respective enzymes (for mutation references, see http://www.genet. Login to comment 77 ABCC7 p.Tyr1092* ABCC7 p.Ile336Lys RESULTS CFTR Screening In 3/20 (15.0%, CI: 5.2-36.0%) patients a CFTR mutation (⌬F508, I336K, Y1092X) known to cause a phenotypical severe clinical course of cystic fibrosis was detected (p Ͻ 0.05 compared to expected frequency of 4%). Login to comment 78 ABCC7 p.Arg75Gln ABCC7 p.Arg75Gln ABCC7 p.Arg75Gln ABCC7 p.Ile336Lys In four patients two potentially predisposing variants, 1716G3A and R75Q, were also present, one of these being compound heterozygous for I336K and R75Q, whereas the other two carried only R75Q or 1716G3A. Login to comment 89 ABCC7 p.Arg75Gln ABCC7 p.Arg75Gln ABCC7 p.Tyr1092* ABCC7 p.Ile336Lys Characteristics of the Study Population Patient Gender CFTR Genotype PolyT Genotype Age at Study, Yr Age at Onset of Disease, Yr Inclusion Criteria Pseudomonas Antibody* Exocrine Insufficiency† Morphological Changes‡ S. K. F I336K/R75Q 7T/7T 34 26 CP 2.44 Yes Mild M. T. M Y1092X/wt 7T/7T 34 30 CP 1.06 Yes Moderate K. M. M R75Q/wt 7T/7T 24 19 RAP 0.46 No Mild L. A. F 1716G3A/wt 7T/7T 27 26 RAP 0.45 No Normal C. B. F ⌬F508/wt 7T/9T 40 38 CP 0.84 No Mild W. O. M 1716G3A/wt 7T/7T 31 29 RAP 0.86 No Normal L. M. F wt/wt 5T/7T 37 27 CP 1.25 Yes Moderate H. K. F wt/wt 7T/7T 27 20 CP 0.84 Yes Mild K. A. M wt/wt 7T/7T 24 19 CP 0.57 Yes Mild H. K. M wt/wt 7T/7T 23 19 CP 0.58 Yes Severe E. H. M wt/wt 7T/7T 25 20 RAP 1.36 No Normal M. K. F wt/wt 7T/7T 35 30 CP 0.55 No Moderate W. S. M wt/wt 7T/7T 19 19 RAP 0.58 No Normal L. D. F wt/wt 7T/7T 33 30 CP 1.07 Yes Severe S. Login to comment 104 ABCC7 p.Arg75Gln ABCC7 p.Ile336Lys Family Study of CFTR In the compound heterozygous patient S.K., we investigated the parents and the sister of this patient for the presence of the missense substitutions R75Q and I336K. Login to comment 106 ABCC7 p.Ile336Lys DNA analysis determined the mutation I336K in patient S.K. and her sister; the mutation had been inherited from their mother. Login to comment 107 ABCC7 p.Arg75Gln On the other hand, missense substitution R75Q was found on the paternal CFTR allele of the patient S.K., which was different from the paternal CFTR allele of her sister (Fig. Login to comment 110 ABCC7 p.Arg117His Neither the known mutations (R117H, N21I, K23R, A16V, D22G) nor any new mutations were present. Login to comment 117 ABCC7 p.Arg117His Increased trypsin activity may either be achieved by reduced autolysis (R117H), acid stability (N21I), facilitated activation of trypsinogen to trypsin (D22G, K23R), or intracellular transport defects (A16V). Login to comment 124 ABCC7 p.Arg75Gln ABCC7 p.Arg75Gln ABCC7 p.Tyr1092* ABCC7 p.Ile336Lys Results of Sweat Test, Intestinal Current Measurement Test, and Anamnestic Features of Patients With Idiopathic Recurrent Acute or Chronic Pancreatic Disease and an Abnormal CFTR Allele Patient CFTR Genotype PolyT Genotype Sweat Chloride (mmol/L) Intestinal Current Measurement (␮A/cm2 )* Anamnestic Features Known to be Associated With Atypical CF S. K. I336K/R75Q 7T/7T 26 50 Nasal polyps M. T. Y1092X/wt 7T/7T 42 27 K. M. R75Q/wt 7T/7T 61 31 L. A. Login to comment 136 ABCC7 p.Ile336Lys Restriction enzyme analysis of exon 7 with SspI detected an atypical band at 410 bp (panel A), suggesting a heterozygosity for I336K. Login to comment 137 ABCC7 p.Ile336Lys Further direct sequence analysis (panel B) showed an exchange of thymidin (T) to adenine (A) at position 1139, confirming the presence of mutation I336K (37). Login to comment 143 ABCC7 p.Arg117His This is supported by recent evidence that patients with chronic alcoholic pancreatitis do not carry the R117H and N21I mutations (23). Login to comment 151 ABCC7 p.Tyr1092* ABCC7 p.Ile336Lys In addition, we detected the mutations I336K and Y1092X, which have not been described before, in patients with idiopathic pancreatitis. Login to comment 155 ABCC7 p.Arg75Gln ABCC7 p.Arg75Gln ABCC7 p.Ile336Lys The missense substitution R75Q was found in two unrelated pancreatitis patients (10%), one of them compound heterozygous for R75Q/I336K. Login to comment 156 ABCC7 p.Arg75Gln In a previous study, we had identified R75Q in two CBAVD patients and in 4% of random control individuals from the German population (17). Login to comment 157 ABCC7 p.Arg75Gln In another report, R75Q has been detected in six CF patients, five of them showing very mild symptoms of the disease (30). Login to comment 158 ABCC7 p.Arg75Gln ABCC7 p.Arg75Gln ABCC7 p.Arg75Gln Although another patient with severe CF was found to carry a second-site mutation on the R75Q allele, no further mutation apart from R75Q could be discovered in the five mildly affected patients. It has been suggested that the R75Q missense substitution represents a borderline CF mutation, which may need additional environmental factors to trigger the disease (30). Login to comment 159 ABCC7 p.Arg75Gln Further studies of larger cohorts are required to clarify the role and relevance of the R75Q substitution in the etiology of cystic fibrosis and pancreatic disease. Login to comment 182 ABCC7 p.Arg75Gln ABCC7 p.Ile336Lys The fact that the paternal CFTR allele from our patient S.K. harboring the R75Q substitution is different from the paternal CFTR allele of her sister-who, like her mother, carries the I336K mutation without having developed pancreatitis-supports this theory. Login to comment