ABCMdb

PMID: 17329263

Ratbi I, Legendre M, Niel F, Martin J, Soufir JC, Izard V, Costes B, Costa C, Goossens M, Girodon E
Detection of cystic fibrosis transmembrane conductance regulator (CFTR) gene rearrangements enriches the mutation spectrum in congenital bilateral absence of the vas deferens and impacts on genetic counselling.
Hum Reprod. 2007 May;22(5):1285-91. Epub 2007 Feb 28., [PubMed]

Sentences

No. Mutations Sentence Comment

15 ABCC7 p.Arg117His The most frequent are the main CF-associated defect, F508del (21-40% of alleles in CBAVD patients, depending on studies), and two mild defects, the T(5) variant of the polypyrimidin tract of the intron 8 (IVS8) acceptor splice site (19-37%) and R117H (3-14%). Login to comment 49 ABCC7 p.Arg75Gln Apart from the IVS8(T)5 variant, sequence variations which are reported as neutral because of segregation analysis in CF families or their frequency in the general population (Bombieri et al., 2000) (such as 356G.A (R75Q), 1540A.G (M470V) or 1716G.A) were not considered as disease-causing when found in isolation. Login to comment 50 ABCC7 p.Arg117His ABCC7 p.Trp1282* ABCC7 p.Arg74Trp ABCC7 p.Leu206Trp ABCC7 p.Asp1152His ABCC7 p.Asp443Tyr ABCC7 p.Gly1069Arg ABCC7 p.Val1153Glu ABCC7 p.Gln1352His ABCC7 p.Ala959Val CFTR mutations were detected in 387 out of 444 alleles (87.2%), most of them being previously described in patients with CF of varying severity, CBAVD or other CFTR diseases: 45% of identified alleles consisted of severe CF mutations (e.g. F508del, W1282X, 2183AA.G); 13.8% of mild or variable CF mutations (e.g. L206W, 3272-26A.G, R117H, D1152H); 36.7% of mild CFTR defects which are currently not considered CF-causing (e.g. IVS8(T)5, Q1352H, the complex alleles [D443Y;G576A;R668C] and [R74W;D1270N]) and 4.5% of rare missense mutations whose effect is difficult to predict (e.g. A959V, G1069R, V1153E). Login to comment 53 ABCC7 p.Val562Ile In five out of the 14 patients carrying the (TG)11(T)5 allele, V562I was also identified, probably in cis as documented in two of these cases and in other patients who do not have CBAVD (Girodon et al., unpublished data). Login to comment 62 ABCC7 p.Val938Gly Patient #2, heterozygous for the mild V938G missense mutation, had a deletion of exons 22 and 23, for which sequencing analysis showed the same breakpoints as those previously described (Audre´zet et al., 2004). Login to comment 63 ABCC7 p.Arg117His Patient #3 had already been referred to in Niel et al. (2004): he was apparently homozygous for R117H with IVS8(T)7 in cis and was found to carry a complete deletion of the CFTR gene, inherited from his mother. Login to comment 67 ABCC7 p.Arg117His Rearrangements, found in 6.9% of 58 unknown alleles (57 alleles from the first two groups of patients and one allele from the patient who was apparently homozygous for R117H), thus accounted for 0.9% of CBAVD alleles and 1% of the identified alleles. Login to comment 69 ABCC7 p.Arg74Trp ABCC7 p.Arg74Trp ABCC7 p.Arg74Trp ABCC7 p.Leu206Trp ABCC7 p.Asp1152His ABCC7 p.Arg668Cys ABCC7 p.Arg668Cys ABCC7 p.Gly576Ala ABCC7 p.Asp443Tyr ABCC7 p.Val562Ile Frequent cystic fibrosis transmembrane conductance regulator (CFTR) defects found in congenital bilateral absence of the vas deferens (CBAVD) patients (above 1% among the identified alleles) Mutation No. of alleles % of the 390 identified alleles F508dela 119 30.5 IVS8(T)5a,b 107 27.4 (TG)12(T)5 82 (TG)13(T)5 16 (TG)11(T)5b 9 R117Ha 25 6.4 R668C 9 2.3 [D443Y;G576A;R668C] 6 [G576A;R668C] 2 R668C 1 L206W 7 1.8 D1152H 6 1.5 W1282Xa 5 1.3 [V562I;(TG)11(T)5] 5 1.3 [R74W;D1270 N] 4 1.0 [R74W;D1270 N] 3 [R74W;V201M;D1270 N] 1 Q1352H(G . Login to comment 71 ABCC7 p.Val562Ile b Do not include the [V562I;(TG)11(T)5] complex alleles that are indicated below. Login to comment 83 ABCC7 p.Asp443Tyr 2 [D443Y;G576A;R668C] þ [?] Login to comment 84 ABCC7 p.Gly576Ala 1 [G576A;R668C] þ [?] Login to comment 85 ABCC7 p.Arg668Cys 1 [R668C] þ [?] Login to comment 88 ABCC7 p.Arg170His 2 [R170H] þ [?] Login to comment 89 ABCC7 p.Val938Gly 1 [V938G] þ [?] Login to comment 90 ABCC7 p.Ala959Val 1 1 [A959V] þ [?] Login to comment 91 ABCC7 p.Gly1069Arg 1 [G1069R] þ [?] Login to comment 92 ABCC7 p.Val1153Glu 1 [V1153E] þ [?] Login to comment 93 ABCC7 p.Arg117His ABCC7 p.Arg334Trp ABCC7 p.Asp1152His ABCC7 p.Met952Ile ABCC7 p.Gly622Asp ABCC7 p.Leu997Phe ABCC7 p.Val232Asp ABCC7 p.Ser977Phe ABCC7 p.Tyr1032Cys ABCC7 p.Glu1473* 1 Two CFTR mutations 15 0-15 0 [R117H] þ [(TG)13(T)5] 1 [R117H] þ [(TG)12(T)5] 1 [R117H] þ [(TG)11(T)5] 1 [R117H] þ [M952I] 1 [D1152H] þ [(TG)12(T)5] 2 [D1152H] þ [Y1032C] 1 [(TG)11(T)5;V562I] þ [L997F] 1 [(TG)11(T)5;V562I] þ [S977F] 1 [E1473X] þ [(TG)13(T)5] 1 [V232D] þ [(TG)12(T)5] 1 [R334W] þ [(TG)12(T)5] 1 [G622D] þ [(TG)12(T)5] 1 [3272-26A . Login to comment 95 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg74Trp ABCC7 p.Arg74Trp ABCC7 p.Asp110His ABCC7 p.Asp110His ABCC7 p.Ile556Val C)] þ [I556V] 1 Apparent homozygosity 3 0-3 1 [R117H] þ [R117H] 1 1 [D110H] þ [D110H] 1 [R74W;D1270 N] þ [R74W;D1270 N] 1 Total 61 57-75 4 F508del, 2221dupA, as well as variants at the IVS8(TG)m(T)n polymorphic site. Login to comment 113 ABCC7 p.Arg117His ABCC7 p.Val938Gly Phenotype and genotype data of patients carrying CFTR rearrangements Patient Current age (years) Origin Allele 1 Allele2 Reference Simple name Extent 1 45 Syria (TG)12(T)5 CFTRdele17a_18 8.6 kb deletion Lerer et al. (1999) 2 33 France/Southern Italy V938G CFTRdele22_23 1.5 kb deletion Audre´zet et al. (2004) 3 47 France R117H CFTRdele1_24 3 Mb deletion This study and Niel et al. (2004) 4 34 Morocco (TG)12(T)5 CFTRdup11_13 Unknown (4.9-35.2 kb duplication) This study Figure 1. Login to comment 124 ABCC7 p.Arg117His A complete CFTR gene deletion was found in one patient who had previously been referred to in Niel et al. (2004) and who was apparently homozygous for R117H. Login to comment 142 ABCC7 p.Val562Ile (TG)11(T)5 penetrance reaching only 11% (Groman et al., 2004), we systematically investigated the whole CFTR gene to look for other cis mutations in the 14 patients carrying this variant and we found V562I in five of them. Login to comment 143 ABCC7 p.Trp1282* ABCC7 p.Leu997Phe ABCC7 p.Ser977Phe Three of the five carried a mutation on the other chromosome: L997F, S977F and W1282X. Login to comment 144 ABCC7 p.Trp1282* ABCC7 p.Val562Ile ABCC7 p.Val562Ile Although V562I has been considered a severe CF mutation, a series of arguments question its severe deleterious effect: its presence in trans of the severe W1282X mutation, the case of a V562I homozygous CF patient who carried in cis the frameshift 2347delG (Girodon et al., unpublished data), and the fact that residue V562 is not conserved in other proteins containing the ATP-binding cassette motif. Login to comment 145 ABCC7 p.Val562Ile We suggest reconsidering V562I as a mild and CBAVD-associated mutation. Login to comment 146 ABCC7 p.Arg117His CBAVD genotypes were varied, the most frequent combined F508del either with the IVS8(T)5 variant (28.0% of 222) or with R117H (6.3%). Login to comment 149 ABCC7 p.Leu206Trp ABCC7 p.Asp1152His Some genotypes had already been described in patients with moderate or late CF, such as those combining F508del with L206W, D1152H, 3272-26A.G or 2789 þ 5G.A. Login to comment 152 ABCC7 p.Arg117His ABCC7 p.Arg74Trp ABCC7 p.Leu997Phe Moreover, genotypes combining two mild alleles were found, such as [R117H] þ [(TG)13(T)5], [(TG)11(T)5;V562I] þ [L997F] or homozygosity for [R74W;D1270N]. Login to comment