ABCMdb

PMID: 11462247

Castellani C, Gomez Lira M, Frulloni L, Delmarco A, Marzari M, Bonizzato A, Cavallini G, Pignatti P, Mastella G
Analysis of the entire coding region of the cystic fibrosis transmembrane regulator gene in idiopathic pancreatitis.
Hum Mutat. 2001 Aug;18(2):166., [PubMed]

Sentences

No. Mutations Sentence Comment

7 ABCC7 p.Ser1235Arg ABCC7 p.Leu997Phe ABCC7 p.Leu997Phe ABCC7 p.Leu997Phe ABCC7 p.Asp614Gly Six possibly CF-related mutations were detected: L997F and 3878delG were found in two of the subjects already carrying another mutation, S1235R and L997F in one patient carrying the 5T, and L997F and D614G in the two patients with borderline sweat chloride. Login to comment 41 ABCC7 p.Arg117His ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Arg347Pro ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Arg352Gln ABCC7 p.Gly85Glu ABCC7 p.Gln552* Genetic analysis Phase 1 - Patients were tested for the following mutations: F508del, I507del, R117H, R1162X, 2183AA>G, N1303K, 3849+10KbC>T, G542X, 1717-1G>A, R347P, R352Q, R553X, Q552X, G85E, 711+5G>A, W1282X, 3132delTG and 2789+5G>A, plus the CFTR intron 8 poly(T) tract length. Login to comment 43 ABCC7 p.Arg117His ABCC7 p.Arg347Pro ABCC7 p.Arg352Gln The same genetic screening, with the exception of the R347P, R352Q, R117H mutations and of the poly(T) variant, was performed in the control population. Login to comment 44 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His All the mutations were analyzed by a Reverse Dot Blot Assay based on those described by Chehab et al (Chehab et al, 1992), with the exception of R117H, for which we used a restriction site generating PCR (Gasparini et al, 1992), and designed two primers: R117H-D [ACC CGG ATA ACA AGG AGG AGC] and R117H-R [GGC CTG TGC AAG GAA GTA TT] which create a CfoI restriction site when the mutation is absent. Login to comment 52 ABCC7 p.Arg553* ABCC7 p.Arg1162* Two patients (2.9%) were compound heterozygotes, 9 (13.4%) had mutations in only one allele (∆F508 in five cases, R553X, 2789+5G→A, R1162X, and 3849+10KbC→T in one case each). Login to comment 63 ABCC7 p.Arg117His ABCC7 p.Arg553* ABCC7 p.Asn1303Lys ABCC7 p.Arg1162* PATIENT A B C Sex (m/f) f f f Age (yrs) 27 60 53 Pancreatitis ICP IRAP IRAP CFTR mutations R1162X 2789+5G→A N1303K R117H R553X PolyT Splice Variant 7/7 7/9 7/9 Sweat Cl- (mEq/l) 108 42 91.75 Sweat Na+ (mEq/l) 106.5 42.8 84.25 NPD n.a. Basal and activated positive Basal negative, activated positive CF-compatible anamnestical and clinical features Chronic cough Lobectomy for bronchiectasis; hemoptysis and bronchial artery embolization Lobar atelectasis Sputum culture Staphylococcus aureus; Pseudomonas aeruginosa Staphylococcus aureus Staphylococcus aureus; Pseudomonas aeruginosa FVC (% predicted) 94 107 118 FEV1 (% predicted) 79 93 116 FEF25-75 (% predicted) 45 49 127 Chest X-ray Chrispin-Norman score 4 3 5 X-ray mucosal thickening of paranasal sinuses Maxillary bilateral Frontal bilateral Maxillary right Weight Z-score -0.86 0.08 -0.53 Height Z-score -0.28 -0.45 -0.12 Pancreatic evaluation § * Pancreatic sufficiency Pancreatic sufficiency n.a. : not available § : duodenal outputs of bicarbonate, lipase, amylase, trypsin and chymotrypsin assessed by pancreatic stimulation test * : normal fecal chymotrypsin and 72-hour steatorrhea The medical history disclosed in 20/53 (37.7%) cases one or more signs and symptoms frequently found in CF: diabetes in 9, sinusitis in 8, chronic cough in 7, malnutrition in 1, monolateral seminal vesicle agenesis in 1, lobectomy secondary to bronchiectasis in 1 and lobar atelectasis in 1 subject. Login to comment 73 ABCC7 p.Ser1235Arg ABCC7 p.Leu997Phe ABCC7 p.Leu997Phe ABCC7 p.Leu997Phe ABCC7 p.Asp614Gly Six possibly CF-related mutations were detected: L997F and 3878delG (the latter described here for the first time) were found in two of the subjects already carrying another mutation, S1235R and L997F in one patient carrying the 5T allele, and L997F and D614G in two of the three patients with borderline sweat chloride. Login to comment 77 ABCC7 p.Arg1162* ABCC7 p.Ser1235Arg ABCC7 p.Leu997Phe ABCC7 p.Leu997Phe ABCC7 p.Leu997Phe ABCC7 p.Asp614Gly Sex (m/f) Age (yr) Pancreatitis CFTR Testing for 18 mutations Newly found mutations after DGGE PolyT Splice Variant Sweat Cl- (mEq/l) Nasal Potential Difference CF-compatible anamnestical and clinical features Sputum culture FEV1 (%) 1 m 17 ICP F508del L997F 7/9 23.5 n.a. - neg. 141 2 m 33 ICP F508del 7/9 n.a. n.a. - n.a. n.a. 3 m 45 ICP 2789+5G→A 7/7 59.5 n.a. - neg. 71 4 f 52 ICP F508del 7/9 28.5 basal and activated: negative - neg. 107 5 m 18 IRAP R1162X 7/7 n.a. n.a. sinusitis n.a. n.a. 6 m 45 ICP F508del 7/9 55.5 basal negative diabetes 7 m 50 ICP F508del 7/9 n.a. n.a. - n.a. n.a. 8 m 14 IAP 3849+10KbC→T 3878delG* 7/7 n.a. n.a. - n.a. n.a. 9 m 27 ICP - S1235R L997F 5/7 24.5 basal and activated: negative - neg. n.a. 10 m 32 IRAP - 5/7 n.a. n.a. - n.a. n.a. 11 f 24 ICP - 5/7 57.5 basal and activated: negative - neg. n.a. 12 f 7 IRAP - 5/7 9.5 basal negative - n.a. n.a. 13 m 28 ICP - L997F 7/9 49.5 n.a. chronic cough n.a. n.a. 14 f 27 IRAP - D614G 7/7 56 n.a. chronic cough, sinusitis neg. 117 n.a. : not available * : novel mutation DISCUSSION There is general agreement that a diagnosis of CF can be formulated in presence of one or more consistent phenotypic features (including pancreatitis) plus the evidence of CFTR dysfunction as documented by elevated sweat chloride concentrations, or identification of two CF-causing mutations, or the in vivo demonstration of abnormal ion transport across the nasal epithelium (Rosenstein et al, 1998). Login to comment 81 ABCC7 p.Arg117His ABCC7 p.Asn1303Lys She is a compound heterozygote, carrying N1303K and R117H. Login to comment 82 ABCC7 p.Arg117His A close association between the latter mutation chromosomal background and its phenotype has been demonstrated (Kiesewetter et al, 1993): R117H, provided it is paired with CF-causing mutations, usually results in CF when in cis with the 5T allele, and in CBAVD when in cis with the 7T allele. Login to comment 103 ABCC7 p.Leu997Phe A peculiar result of the study was the finding in three occasions of L997F, a mutation otherwise rare in CF, but perhaps more common in idiopathic disseminated bronchiectasis and in hypertrypsinemic newborns with normal sweat chloride levels (Bombieri et al, 1998; Gomez Lira et al, 2000). Login to comment 104 ABCC7 p.Leu997Phe Having speculated that L997F could in some way be associated with the pancreatitis phenotype, it was sought in a further 18 patients from phase 1, and one of them tested positive: this mutation was therefore found in 9/32 patients with idiopathic pancreatitis (Gomez Lira et al, 2000). Login to comment 105 ABCC7 p.Ser1235Arg ABCC7 p.Asp614Gly As for the other mutations found in phase 2, 3878delG had not been described previously, D614G had been found in exon 13 of a CF patient from Italian origin, and S1235R in exon 19 in two out of 34 unrelated Belgian CF chromosomes (Cystic Fibrosis Genetic Analysis Consortium, http://www.genet.sickkids.on.ca./cftr). Login to comment