ABCMdb

PMID: 18703181

Brugnon F, Bilan F, Heraud MC, Grizard G, Janny L, Creveaux I
Outcome of intracytoplasmic sperm injection for a couple in which the man is carrier of CFTR p.[R74W;V201M;D1270N] and p.P841R mutations and his spouse a heterozygous carrier of p.F508del mutation of the cystic fibrosis transmembrane conductance regulator gene.
Fertil Steril. 2008 Nov;90(5):2004.e23-6. Epub 2008 Aug 13., [PubMed]

Sentences

No. Mutations Sentence Comment

0 ABCC7 p.Arg74Trp ABCC7 p.Arg74Trp ABCC7 p.Arg74Trp ABCC7 p.Pro841Arg ABCC7 p.Pro841Arg ABCC7 p.Pro841Arg CASE REPORT Outcome of intracytoplasmic sperm injection for a couple in which the man is carrier of CFTR p.[R74W;V201M;D1270N] and p.P841R mutations and his spouse a heterozygous carrier of p.F508del mutation of the cystic fibrosis transmembrane conductance regulator gene Florence Brugnon, M.D.,a Frederic Bilan, Ph.D.,b Marie-Christine Heraud, M.D.,c Genevieve Grizard, Ph.D.,a Laurent Janny, M.D.,a and Isabelle Creveaux, M.D., Ph.Dd a CHU Clermont-Ferrand, Biologie du Developpement et de la Reproduction, CECOS, H^otel Dieu, Clermont Ferrand; b CHU Poitiers, Laboratoire de Genetique Cellulaire et Moleculaire, Universite de Poitiers, UFR Medecine-Pharmacie, Poitiers; c CHU Clermont Ferrand, Pediatrie A, H^otel Dieu; and d CHU Clermont Ferrand, Laboratoire de biochimie medicale et biologie moleculaire, Faculte de Medecine, Clermont Ferrand, France Objective: To document the phenotype associated with the p.[R74W;V201M;D1270N] and p.P841R mutations of cystic fibrosis transmembrane conductance regulator (CFTR) gene. Login to comment 3 ABCC7 p.Arg74Trp ABCC7 p.Pro841Arg Patient(s): A couple in which the man is carrier of the triple mutant p.[R74W;V201M;D1270N] allele in trans to p.P841R mutation and his spouse a heterozygous carrier for the severe p.F508del mutation of the CFTR gene, who became pregnant after intracytoplasmic sperm injection (ICSI) with twins. Login to comment 5 ABCC7 p.Pro841Arg Main Outcome Measure(s): First report of a male phenotype associated with the p.P841R mutation. Login to comment 6 ABCC7 p.Arg74Trp ABCC7 p.Pro841Arg ABCC7 p.Pro841Arg Result(s): The triple mutant p.[R74W;V201M;D1270N] allele associated with the unknown p.P841R mutations were detected in this man with congenital bilateral absence of the vas deferens, which may presume p.P841R as a severe mutation. Login to comment 7 ABCC7 p.Arg74Trp After genetic counseling, the couple preferred prenatal diagnosis after ICSI than preimplantation genetic diagnosis, which revealed that the boys were both carriers of p.[R74W;V201M;D1270N] and p.F508del mutations. Login to comment 9 ABCC7 p.Pro841Arg Conclusion(s): This case report documents for the first time a male phenotype associated with the p.P841R mutation and underlines the difficulties in counseling a man with congenital bilateral absence of the vas deferens carrying uncommon mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene before ICSI. Login to comment 12 ABCC7 p.Arg74Trp ABCC7 p.Pro841Arg Key Words: CFTR, [p.R74W;p.V201M;p.1270N], p.P841R, genetic counseling, ICSI, CBAVD Treatment by assisted reproductive technology (ART) of infertile men with congenital bilateral absence of the vas deferens (CBAVD) associated with mutations of the CFTR gene changed after the introduction of intracytoplasmic sperm injection (ICSI) with epididymal or testicular spermatozoa (1). Login to comment 16 ABCC7 p.Arg74Trp ABCC7 p.Pro841Arg ABCC7 p.Pro841Arg The purpose of this case report is to describe and analyze the outcome of an infertile couple in which the man with CBAVD is carrier of rare mutations of the CFTR gene p.[R74W;V201M;D1270N] þ p.P841R and his spouse, a heterozygous carrier for F508del. Login to comment 17 ABCC7 p.Pro841Arg To our knowledge, this is the first report that describes the phenotype of an infertile man with CBAVD carrying p.P841R. Login to comment 26 ABCC7 p.Arg74Trp Fertility and Sterility Vol. 90, No. 5, November 2008 0015-0282/08/$34.00 Copyright &#aa;2008 American Society for Reproductive Medicine, Published by Elsevier Inc. doi:10.1016/j.fertnstert.2008.05.057 2004.e23 p.[R74W;V201M;D1270N] allele was previously reported in men with CBAVD (3), but never in symptomatic patients with CF. Login to comment 27 ABCC7 p.Arg74Trp doi:10.1016/j.fertnstert.2008.05.057 2004.e23 p.[R74W;V201M;D1270N] allele was previously reported in men with CBAVD (3), but never in symptomatic patients with CF. Login to comment 39 ABCC7 p.Arg74Trp ABCC7 p.Pro841Arg Results revealed that the man was a compound heterozygous carrier of the triple mutant p.[R74W;V201M;D1270N] allele and the unknown p.P841R mutation (Fig. 1) and his spouse was a heterozygous carrier for p.F508del. Login to comment 40 ABCC7 p.Arg74Trp ABCC7 p.Arg74Trp ABCC7 p.Pro841Arg ABCC7 p.Pro841Arg Results revealed that the man was a compound heterozygous carrier of the triple mutant p.[R74W;V201M;D1270N] allele and the unknown p.P841R mutation (Fig. Login to comment 41 ABCC7 p.Pro841Arg To our knowledge the significance of CFTR p.P841R has never been described to date, and its functional significance is unknown. Login to comment 42 ABCC7 p.Arg74Trp ABCC7 p.Pro841Arg Segregation analysis of the man`s parents revealed that his father transmitted the CFTR p.P841R mutation and his mother, the complex allele p.[R74W;V201M;D1270N]. Login to comment 43 ABCC7 p.Pro841Arg To our knowledge the significance of CFTR p.P841R has never been described to date, and its functional significance is unknown. Login to comment 47 ABCC7 p.Arg74Trp At 22 weeks gestation, prenatal diagnosis revealed that the two male fetuses carried not only the triple mutant allele p.[R74W;V201M;D1270N] inherited from their father but also p.F508del from their mother. Login to comment 49 ABCC7 p.Arg74Trp At 22 weeks gestation, prenatal diagnosis revealed that the two male fetuses carried not only the triple mutant allele p.[R74W;V201M;D1270N] inherited from their father but also p.F508del from their mother. Login to comment 51 ABCC7 p.Asp1270Asn ABCC7 p.Arg74Trp Electrophoregrams of the sequencing products obtained in the patient showing heterozygous profiles for the p.D1270N, p.R74W, and the newly identified p.841R mutations (indicated by red arrow in each figure). Login to comment 52 ABCC7 p.Asp1270Asn ABCC7 p.Arg74Trp ABCC7 p.Pro841Arg (a) p.D1270N mutation (3940 G>A); (b) p.R74W mutation (352 C>T); (c) p.P841R mutation (2854 C>G). Login to comment 53 ABCC7 p.Asp1270Asn ABCC7 p.Arg74Trp Electrophoregrams of the sequencing products obtained in the patient showing heterozygous profiles for the p.D1270N, p.R74W, and the newly identified p.841R mutations (indicated by red arrow in each figure). Login to comment 54 ABCC7 p.Asp1270Asn ABCC7 p.Arg74Trp ABCC7 p.Pro841Arg (a) p.D1270N mutation (3940 G>A); (b) p.R74W mutation (352 C>T); (c) p.P841R mutation (2854 C>G). Login to comment 63 ABCC7 p.Pro841Arg Nevertheless, it is extremely difficult to predict the risks of inheritance of uncommon or newly identified mutations whose phenotype has never been described, such as the p.P841R mutation. Login to comment 64 ABCC7 p.Pro841Arg The p.P841R mutation leads to the substitution of a proline for an arginine in exon 14a. Login to comment 65 ABCC7 p.Pro841Arg Nevertheless, it is extremely difficult to predict the risks of inheritance of uncommon or newly identified mutations whose phenotype has never been described, such as the p.P841R mutation. Login to comment 66 ABCC7 p.Pro841Arg The p.P841R mutation leads to the substitution of a proline for an arginine in exon 14a. Login to comment 68 ABCC7 p.Arg74Trp The CBAVD phenotype of this infertile patient could indicate that this mutation may be severe or mild, as the triple mutant p.[R74W;V201M;D1270N] is considered as a mild one, and as it was described in CBAVD patients in trans with severe mutations. Login to comment 69 ABCC7 p.Asp1270Asn Since the beginning of population screening for CF carriers, new datahavedemonstratedthattheprevalenceofcertaincom- plex alleles like p.[D1270N;p.R74W] is high (6). Login to comment 70 ABCC7 p.Arg74Trp The CBAVD phenotype of this infertile patient could indicate that this mutation may be severe or mild, as the triple mutant p.[R74W;V201M;D1270N] is considered as a mild one, and as it was described in CBAVD patients in trans with severe mutations. Login to comment 71 ABCC7 p.Asp1270Asn ABCC7 p.Asp1270Asn Since the beginning of population screening for CF carriers, new datahavedemonstratedthattheprevalenceofcertaincom- plex alleles like p.[D1270N;p.R74W] is high (6). Login to comment 72 ABCC7 p.Asp1270Asn ABCC7 p.Arg74Trp Initially p.R74W and p.D1270N were described in isolation but they have since been found in association in many men with CBAVD (3, 7). Login to comment 73 ABCC7 p.Asp1270Asn ABCC7 p.Asp1270Asn ABCC7 p.Arg74Trp ABCC7 p.Arg74Trp ABCC7 p.Arg74Trp Thus p.D1270N was found more frequently (6) in carrier screening than in patients with CF (frequency 14% vs. 0.068%). Login to comment 74 ABCC7 p.Asp1270Asn ABCC7 p.Asp1270Asn ABCC7 p.Asp1270Asn ABCC7 p.Arg74Trp ABCC7 p.Arg74Trp ABCC7 p.Arg74Trp Initially p.R74W and p.D1270N were described in isolation but they have since been found in association in many men with CBAVD (3, 7). Login to comment 75 ABCC7 p.Asp1270Asn ABCC7 p.Arg74Trp ABCC7 p.Arg74Trp ABCC7 p.Arg74Trp Structure function analysis demonstrated that when they are expressed in HeLa cells; mutants p.R74W, p.D1270N, and p.[R74W;D1270N] do not affect CFTR processing.However,lowercyclicadenosine30 :50 monophosphate (cAMP) responsive anion conductance was observed with the double mutant p.[R74W;D1270N]. Login to comment 76 ABCC7 p.Asp1270Asn ABCC7 p.Asp1270Asn ABCC7 p.Asp1270Asn ABCC7 p.Asp1270Asn ABCC7 p.Arg74Trp ABCC7 p.Arg74Trp ABCC7 p.Arg74Trp ABCC7 p.Arg74Trp This study suggested that mutant p.R74Walone could be considered as a polymorphism, p.D1270N alone could generate a CBAVD phenotype, whereas the complex allele p.[R74W;D1270N] may produce a more severe phenotype because p.R74W could enhance the effect of p.D1270N (8). Login to comment 78 ABCC7 p.Asp1270Asn ABCC7 p.Asp1270Asn ABCC7 p.Arg74Trp ABCC7 p.Arg74Trp ABCC7 p.Arg74Trp Compound heterozygote for p.D1270N has been identified in asymptomatic adults (6), whereas individuals carrying p.D1270N associated with p.R74W on the same allele (p.[R74W;D1270N]) have not been found among asymptomatic (3) or among men with CBAVD (7). Login to comment 80 ABCC7 p.Arg74Trp ABCC7 p.Arg74Trp The alteration found for our patient is a triple mutant allele p.[R74W;V201M;D1270N]. Login to comment 82 ABCC7 p.Arg74Trp ABCC7 p.Arg74Trp ABCC7 p.Pro841Arg The CBAVD phenotype described in homozygous p.[R74W;V201M;D1270N] patients (3) suggests that we can consider this triple mutant allele as mild. Login to comment 84 ABCC7 p.Arg74Trp ABCC7 p.Pro841Arg During genetic counseling before ICSI, the couple was given explanations concerning the high risk of CF for the children if both p.F508del and p.P841R were inherited, respectively, from their mother and father, and the risk of CBAVD if p.[R74W;V201M;D1270N] and p.F508del were inherited. Login to comment 86 ABCC7 p.Pro841Arg If the fetus were found to be a carrier of p.P841R and p.F508del, the couple was offered therapeutic abortion, given the high risk of CF for the offspring. Login to comment 88 ABCC7 p.Pro841Arg If the fetus were found to be a carrier of p.P841R and p.F508del, the couple was offered therapeutic abortion, given the high risk of CF for the offspring. Login to comment 89 ABCC7 p.Arg74Trp Because the twin boys are carriers of this complex association of mutations and that the double complex allele p.[R74W;D1270N] associated with p.F508del has been described before as being associated with a pauci-symptomatic form of CF (9), they are monitored regularly. Login to comment 91 ABCC7 p.Arg74Trp Because the twin boys are carriers of this complex association of mutations and that the double complex allele p.[R74W;D1270N] associated with p.F508del has been described before as being associated with a pauci-symptomatic form of CF (9), they are monitored regularly. Login to comment