ABCMdb

PMID: 15614862

D'Apice MR, Gambardella S, Russo S, Lucidi V, Nardone AM, Pietropolli A, Novelli G
Segregation analysis in cystic fibrosis at-risk family demonstrates that the M348K CFTR mutation is a rare innocuous polymorphism.
Prenat Diagn. 2004 Dec 15;24(12):981-3., 2004-12-15 [PubMed]

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2 ABCC7 p.Met348Lys DOI: 10.1002/pd.1058 Segregation analysis in cystic fibrosis at-risk family demonstrates that the M348K CFTR mutation is a rare innocuous polymorphism Maria Rosaria D`Apice1 , Stefano Gambardella1 , Silvia Russo1 , Vincenzina Lucidi2 , Anna Maria Nardone3 , Adalgisa Pietropolli4 and Giuseppe Novelli1,3 * 1 Department of Biopathology and Imaging Diagnostic, Tor Vergata University, Rome, Italy 2 Bambino Ges`u Children`s Hospital, Rome, Italy 3 Department of Medical Laboratory, Section of Medical Genetics, Tor Vergata University, Rome, Italy 4 Department of Surgery, Section of Obstetrics and Gynaecology, Tor Vergata University, Rome, Italy Objective Cystic fibrosis (CF; OMIM# 219700) is caused by mutation in the CF transmembrane regulator (CFTR) gene. Login to comment 3 ABCC7 p.Asn1303Lys ABCC7 p.Met348Lys We investigate whether the (paternal) M348K mutation is a benign polymorphism or a disease-causing mutation in a patient clinically affected with CF, with the second (maternal) CFTR allele identified as N1303K. Login to comment 6 ABCC7 p.Gly1244Glu ABCC7 p.Met348Lys Results The CFTR gene from the healthy father has two mutations, M348K and G1244E. Login to comment 7 ABCC7 p.Gly1244Glu The affected son inherited only the G1244E paternal mutation from his father, and hence the two paternal mutations are trans and do not occur in the same CFTR gene. Login to comment 10 ABCC7 p.Met348Lys Conclusion M348K in the CFTR gene is not a mutation causing CF, but a rare polymorphism. Login to comment 26 ABCC7 p.Met348Lys This demonstrates that the M348K variation is not a causative CF mutation. Login to comment 28 ABCC7 p.Gly1244Glu ABCC7 p.Gly1244Glu ABCC7 p.Gly1244Glu ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Met348Lys Received: 30 April 2004 Revised: 7 October 2004 Accepted: 10 October 2004 M. R. D`APICE ET AL. 1 1 1 1 3 4 1 2 1 1 4 1 1 2 1 1 4 1 1 2 1 1 2 1I:1 II:1 II:2 I:2 G1244E M348K G1244E N1303K N1303K G1244E N1303K IVS8GT IVS17bCA IVS17bTA IVS8GT IVS17bCA IVS17bTA IVS8GT IVS17bCA IVS17bTA IVS8GT IVS17bCA IVS17bTA Figure 1-The reported family pedigree. Login to comment 29 ABCC7 p.Gly1244Glu ABCC7 p.Asn1303Lys The proband (II:1) and the fetus (II:2) have each inherited G1244E and N1303K. Login to comment 30 ABCC7 p.Gly1244Glu ABCC7 p.Asn1303Lys ABCC7 p.Met348Lys Their asymptomatic father (I:1) shows the G1244E CF mutation and the M348K polymorphism; their mother (I:2) shows the N1303K mutation. Login to comment 34 ABCC7 p.Asn1303Lys The N1303K mutation was identified, and shown to be inherited from the mother (Figure 1). Login to comment 36 ABCC7 p.Gly1244Glu ABCC7 p.Met348Lys Abnormal DHPLC patterns were observed for exons 7 and 20 (Figure 1), caused by nucleotide changes (T to A at position 1175, missense mutation M348K; G to A in position 3863, missense mutation G1244E). Login to comment 38 ABCC7 p.Gly1244Glu ABCC7 p.Gly1244Glu ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys Direct analysis of exons 7 and 20 showed that the patient received only the G1244E paternal mutation and the N1303K maternal mutation giving a genotype N1303K/G1244E. Login to comment 39 ABCC7 p.Gly1244Glu ABCC7 p.Asn1303Lys Analysis using three intragenic microsatellites (IVS8GT, IVS17bTA, IVS17bCA) confirmed that the affected proband inherited the paternal chromosome carrying the G1244E mutation and N1303K from his mother. Login to comment 40 ABCC7 p.Met348Lys The M348K mutation was first reported by Audrezet et al. (1993) in a severely affected Italian patient with pancreatic insufficiency and lung involvement. Login to comment 41 ABCC7 p.Met348Lys ABCC7 p.Leu346Pro However, in another report, Deltas et al. (1996) described a Cypriot individual without symptoms of CF who is compound heterozygous for L346P/M348K. Login to comment 42 ABCC7 p.Gly1244Glu G1244E is a missense mutation in exon 20, peculiar to patients from southern Italy (Castaldo et al., 1999). Login to comment 43 ABCC7 p.Gly1244Glu DISCUSSION The mutation G1244E is known to be found in Italian CF patients and causes moderate to severe disease (Castaldo et al., 1999). Login to comment 44 ABCC7 p.Gly1244Glu ABCC7 p.Gly1244Glu ABCC7 p.Met348Lys Since the father has no symptoms of CF, and has the genotype M348/G1244E, M348K must be a rare polymorphism in the CFTR gene that is not disease-associated, at least in association with G1244E. Login to comment 45 ABCC7 p.Met348Lys If a patient with CF is shown to have the mutation M348K, as in this case, the gene should be scanned for other mutations. Login to comment 46 ABCC7 p.Arg297Gln This is similar to the situation for the R297Q mutation (Dorval et al., 1995). Login to comment 51 ABCC7 p.Gly1244Glu ABCC7 p.Asn1303Lys The fetus (II-2, Figure 1) was compound heterozygous for the N1303K/G1244E mutations and haploidentical to the affected proband. Login to comment 55 ABCC7 p.Met348Lys The M348K amino acid change is a rare polymorphism rather than a CF-causing mutation, as previously reported. Login to comment