ABCMdb

PMID: 25481366

Oueslati S, Hadj Fredj S, Belhaj R, Siala H, Bibi A, Messaoud T
Preliminary study of haplotypes linked to the rare cystic fibrosis E1104X mutation.
Acta Physiol Hung. 2015 Mar;102(1):86-93. doi: 10.1556/APhysiol.101.2014.013., [PubMed]

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0 ABCC7 p.Glu1104* 0231-424X/$ 20.00 (c) 2014 Akad&#e9;miai Kiad&#f3;, Budapest Acta Physiologica Hungarica, Volume 102 (1), pp. 86-93 (2015) DOI: 10.1556/APhysiol.101.2014.013 First published online December 6, 2014 Preliminary study of haplotypes linked to the rare cystic fibrosis E1104X mutation S Oueslati, S Hadj Fredj, R Belhaj, H Siala, A Bibi, T Messaoud Biochemistry Laboratory, Research Laboratory "Haemoglobinopathies and Cystic Fibrosis, LROOSPO3", Children`s Hospital, Tunis, Tunisia Received: February 1, 2012 Accepted after revision: August 29, 2012 The analysis of some extra- and intragenic markers within or closely linked to the cystic fibrosis transmembrane regulator (CFTR) gene is useful as a molecular method in clinical linkage analysis. Login to comment 1 ABCC7 p.Glu1104* Indeed, knowing that the molecular basis of cystic fibrosis (CF) is highly heterogeneous in our population, the study of haplotype association with normal and CF chromosomes could be very helpful in cases where one or both mutations remain unidentified. In this study, we analysed with PCR-RFLP and capillary electrophoresis some extra (pJ3.11, KM19 and XV2C) and intragenic (IVS8CA, IVS17bTA and IVS17bCA) polymorphic markers in 50 normal and 10 Tunisian patients carrying the rare E1104X mutation in order to determine the haplotype associated with this mutation. Login to comment 4 ABCC7 p.Glu1104* For the intragenic markers, five haplotypes were present on the E1104X chromosomes. One of them 16-31-13 accounted for 50%. Login to comment 5 ABCC7 p.Glu1104* To our knowledge, this is the first work to be interested to the haplotypes linked to the E1104X mutation. Login to comment 7 ABCC7 p.Glu1104* Keywords: CF, E1104X mutation, haplotype, extragenic markers, intragenic mark Cystic fibrosis (CF) is the most common lethal autosomal recessive disorder in Caucasian populations. Login to comment 12 ABCC7 p.Glu1104* The E1104X located in exon 17b, is the second mutation after the F508del mutation in our population, represents 16.18% of all CF mutations but it is a rare mutation in the world (9). Login to comment 14 ABCC7 p.Glu1104* The haplotypes associated with the CFTR mutations in the North African population remain unidentified. In this work we aimed to determine haplotypes associated with the E1104X mutation using 3 intragenic microsatellites (IVS8CA, IVS17bTA and IVS17bCA), and 3 extragenic markers (pJ3.11, KM19 and XV2C). Login to comment 20 ABCC7 p.Glu1104* The CFTR mutation was previously identified to be the E1104X mutation using DGGE and sequencing reaction (9). Login to comment 43 ABCC7 p.Glu1104* Results and Discussion The E1104X mutation, initially discovered by Zielenski in a French-Canadian patient in 1992 (http://www.genet.sickkids.on.ca/cftr/), consists of a single nucleotide substitution (G to T) at position 3442 in exon 17b, and causes introduction of a premature stop codon (GAA to TAA) at position 1104 in the protein sequence (27). Login to comment 44 ABCC7 p.Glu1104* The E1104X mutation was later described in Germany by Reiss in 1993 (21), in France (4, 23, 24), and in US (10). Login to comment 46 ABCC7 p.Glu1104* The study of extragenic haplotypes associated with the E1104X allele revealed 8 different haplotypes (Table II). Login to comment 52 ABCC7 p.Glu1104* Five haplotypes were observed in E1104X chromosomes. One of them (16-31-13), accounting for 50%, was strongly associated to this mutation (p = 6.4 10-11 ) (Table III). Login to comment 54 ABCC7 p.Glu1104* Different extragenic haplotypes found in the 120 analyzed chromosomes Haplotype name E1104X mutation Normal P Number of chromosomes % Number of chromosomes % 221 9 45 11 11 0.00019 112 7 35 11 11 0.006 111 2 10 21 21 0.253 222 1 5 23 23 0.066 211 1 5 8 8 0.641 121 - 10 10 212 - 8 8 122 - 8 8 Total 20 100 Haplotype is named according to the absence (1) or presence (2) of restriction site at loci pJ3.11, KM19 and XV2C, respectively A second haplotype (16-30-13) present only in CF chromosomes representing 20% appears also to be highly associated with this mutation (p = 0.00038) (Table III). Login to comment 62 ABCC7 p.Asn1303Lys ABCC7 p.Gly542* The most common CF mutations (F508del, G542X and N1303K), provide an exceptional opportunity for the analysis of association between microsatellite allelic systems and SNP`s. Login to comment 64 ABCC7 p.Glu1104* However, the haplotype analysis linked to rare mutation remains undetermined, that is why in this study we aimed to determine haplotypes associated with the E1104X mutation using some extra (pJ3.11, KM19 and XV2C) and intragenic (IVS8CA, IVS17bTAand IVS17bCA) polymorphic markers. Login to comment 66 ABCC7 p.Glu1104* Our work is the first in the world to be interested to the study of the haplotype linked to the E1104X mutation. Login to comment 68 ABCC7 p.Glu1104* We found it interesting to determine haplotypes associated with the E1104X mutation to provide information on the age and origin of this mutation. Login to comment 70 ABCC7 p.Glu1104* Distribution of the microsatellites haplotypes among normal and CF chromosomes Name of haplotype E1104X mutation Normal P Number of chromosomes % Number of chromosomes % 16-31-13 10 50 2 2 6.4 10-11 16-30-13 4 20 - - 0.00038 16-30-14 2 10 - - 0.013 16-29-14 2 10 1 1 0.018 22-31-14 2 10 4 4 0.261 17-07-17 - 13 13 23-31-13 - 6 6 18-7-13 - 5 5 23-44-15 - 3 3 18-31-13 - 4 4 22-44-13 - 2 2 16-38-13 - 6 6 16-33-13 - 2 2 22-48-13 - 3 3 18-41-13 - 2 2 22-43-13 - 2 2 23-28-17 - 3 3 22-30-13 - 2 2 23-32-15 - 3 3 16-44-13 - 2 2 17-44-11 - 1 1 18-29-16 - 1 1 19-7-17 - 4 4 22-33-13 - 3 3 16-41-17 - 1 1 16-40-15 - 2 2 15-30-13 - 2 2 16-47-14 - 1 1 16-48-13 - 1 1 17-42-14 - 3 3 23-47-13 - 1 1 16-33-15 - 2 2 16-40-17 - 1 1 17-45-13 - 2 2 17-31-11 - 1 1 18-31-15 - 1 1 16-45-13 - 2 2 15-37-13 - 1 1 17-41-13 - 2 2 23-44-11 - 1 1 16-40-11 - 1 1 22-35-17 - 1 1 Each haplotype is named according to the number of repeats at loci IVS8CA, IVS17bTA and IVS17bCA, respectively 91 91 Fig. 1. Login to comment 73 ABCC7 p.Glu1104* For the extragenic haplotype, E1104X mutation is associated in 80% of cases to both 221 and 112 haplotypes. Login to comment 75 ABCC7 p.Glu1104* The E1104X mutation revealed a heterogeneous microsatellite polymorphism profile since it was associated with five different haplotypes. Login to comment 78 ABCC7 p.Ser549Asn ABCC7 p.Glu60* ABCC7 p.Glu1104* The 16-31-13 haplotype found in 50% of E1104X chromosomes was also described linked to 2 rare mutations, the E60X mutation in UK (12) and S549N mutation in the "Grande bri&#e9;re" population (3). Login to comment 80 ABCC7 p.Glu1104* The 23-31-13 haplotype generally associated with the most common mutation F508del (2, 5), was not encountered in the E1104X chromosomes. Login to comment 82 ABCC7 p.Glu1104* On the other hand, the 16-30-13 and 16-30-14 haplotypes not observed in the normal chromosomes could be suggested as specific and sensitive haplotypes for E1104X mutation. Login to comment 88 ABCC7 p.Glu1104* ABCC7 p.Glu1104* The diamond color indicates the level of LD; darker shades indicate a higher LD while lighter shades indicate lower LD and Grey regions represent missing data points This first preliminary study of haploypes linked to E1104X mutation can be completed by the analysis of a large sample of patients with E1104X mutation and other mutations found in Tunisia. Login to comment