ABCMdb

PMID: 9272157

Dork T, Dworniczak B, Aulehla-Scholz C, Wieczorek D, Bohm I, Mayerova A, Seydewitz HH, Nieschlag E, Meschede D, Horst J, Pander HJ, Sperling H, Ratjen F, Passarge E, Schmidtke J, Stuhrmann M
Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens.
Hum Genet. 1997 Sep;100(3-4):365-77., [PubMed]

Sentences

No. Mutations Sentence Comment

7 ABCC7 p.Arg117His Twenty-one German CAVD patients were compound heterozygous for ∆F508 and R117H, which was the most frequent CAVD genotype in our study group. Login to comment 8 ABCC7 p.Arg117His Haplotype analysis indicated a common origin for R117H in our population, whereas another frequent CAVD mutation, viz. the "5T allele" was a recurrent mutation on different intragenic haplotypes and multiple ethnic backgrounds. Login to comment 11 ABCC7 p.Phe508Cys A few splice or missense variants, such as F508C or 1716 G→A, are proposed here as possible candidate CAVD mutations with an apparently reduced penetrance. Login to comment 40 ABCC7 p.Leu375Phe In one family, two brothers were ascertained as having CBAVD and the CFTR genotype ∆F508/L375F. Login to comment 43 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Arg347His ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Tyr1092* ABCC7 p.Arg117Cys ABCC7 p.Ile336Lys This initial screening included the mutations ∆F508, G542X, R553X, G551D, N1303K, 1717-1 G→A, 3272-26 A→G, Y1092X, 2143delT, R347P, R347H, R334W, I336K, R117H, R117C, 2789+5 G→A, 3849+10kB C→T and the "5T" allele, the latter two splice variants being tested according to the instructions of Highsmith et al. (1994) and Chillón et al. (1995). Login to comment 56 ABCC7 p.Arg117His Two CF mutations (∆F508 and R117H) and one splicing variant (the "5T" allele) were found to be particularly common in these patients. Login to comment 58 ABCC7 p.Arg117His Missense substitution R117H was identified on 24 chromosomes (11%), which is an approximately 30-fold increase in allele frequency compared with German CF chromosomes (Dörk et al. 1994b). Login to comment 59 ABCC7 p.Arg117His ABCC7 p.Arg117His This frequency of R117H seems to be the highest number reported so far in a patient subpopulation and confirms a particular association of R117H with the CAVD phenotype in Mid-Europe (Gervais et al. 1993). Login to comment 60 ABCC7 p.Arg117His All the R117H alleles were from patients of German or Austrian descent and carried the same diagnostic marker haplotype composed of four intragenic dimorphisms and the 7T allele (Table 1). Login to comment 61 ABCC7 p.Arg117His This haplotype is otherwise rare on normal or CF chromosomes and accounts for less than 0.5% in the German population, suggesting a common origin of the R117H mutation, which occurs at a CpG dinucleotide, in Mid-European populations. Login to comment 68 ABCC7 p.Arg117His Screening for the three mutations ∆F508, R117H and "5T" together allowed the identification of some 40% of mutations in our CAVD cohort. Login to comment 69 ABCC7 p.Arg347His ABCC7 p.Gly542* Only four other common CF mutations were found in more than one family by this initial screening: 2789+5 G→A on 4 alleles, R347H on 3 alleles, G542X and 3272-26 A→G each on 2 alleles (Table 1). Login to comment 79 ABCC7 p.Glu56Lys ABCC7 p.Glu56Lys The E56K mutation was found in a German CBAVD patient who carried ∆F508 on the maternal allele and E56K on the paternal allele. Login to comment 80 ABCC7 p.Asp58Asn ABCC7 p.Asp58Asn The D58N mutation was uncovered in a Lebanese CBAVD patient who had inherited D58N from his father and a "5T" allele from his mother. Login to comment 81 ABCC7 p.Gln1352His ABCC7 p.Arg297Trp The R297W mutation was identified on a Q1352H chromosome in a Vietnamese CBAVD patient (see below). Login to comment 82 ABCC7 p.Arg334Trp ABCC7 p.Arg334Leu The R334L mutation occurs at a position at which another mutation, R334W, has been described in mild to moderate CF and has been found to affect chloride channel conductivity significantly (Gasparini et al. 1991; Sheppard et al. 1993). Login to comment 83 ABCC7 p.Arg334Leu ABCC7 p.Ile336Lys The German CBAVD patient in our study was compound heterozygous for R334L and for the missense mutation I336K in the same exon. Login to comment 84 ABCC7 p.Asp979Ala ABCC7 p.Val938Gly ABCC7 p.Arg933Ser ABCC7 p.Leu973Phe Six other new missense mutations were located in the carboxyterminal transmembrane domain, particularly in the third cytoplasmic loop (R933S, V938G, L973F, D979A). Login to comment 85 ABCC7 p.Arg75Gln ABCC7 p.Arg933Ser The R933S substitution was found together with the R75Q allele in a heterozygous CBAVD patient who also carried the ∆F508 deletion. Login to comment 86 ABCC7 p.Arg117His ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Arg347His ABCC7 p.Gly542* ABCC7 p.Leu206Trp ABCC7 p.Ala120Thr ABCC7 p.Leu568Phe ABCC7 p.Arg334Leu ABCC7 p.Val938Gly ABCC7 p.Ile336Lys ABCC7 p.Leu375Phe ABCC7 p.Asp110His ABCC7 p.Asp58Asn ABCC7 p.Met265Arg ABCC7 p.Arg297Trp ABCC7 p.Glu56Lys ABCC7 p.Arg933Ser The V938G substitution was identified in two unrelated patients, one homozygote with unilateral ab- 368 Table 1A Frequency distribution and haplotypes of CFTR mutations in 106 CAVD patients Mutationa Nucleotide changesb Locationc Frequencyd Haplotypee Referencef 174delA deletion of A at 174 exon 1 1 D3 This study E56K G→A at 298 exon 3 1 B3 This study D58N G→A at 304 exon 3 1 C2 This study D110H G→A at 460 exon 4 2 C2 Dean et al. (1990) R117H G→A at 482 exon 4 24 B6 Dean et al. (1990) A120T G→A at 490 exon 4 1 n.p. Chillón et al. (1994) ̃L138 insertion of CTA after 546 exon 4 1 A2 This study L206W T→G at 749 exon 6a 1 B8 Claustres et al. (1993) M265R T→G at 926 exon 6b 1 A2 Schwarz et al. (pers. comm.) R297W C→T at 1021 exon 7 1 C2 This study 1078delT deletion of T at 1078 exon 7 1 C2 Claustres et al. (1992) R334W C→T at 1132 exon 7 1 B1 Gasparini et al. (1991) R334L G→T at 1133 exon 7 1 D3 This study I336K T→A at 1139 exon 7 1 A2 Cuppens et al. (1993) R347H G→A at 1172 exon 7 3 D1 Cremonesi et al. (1992) L375F A→C at 1257 exon 8 1 B3 Jézéquel et al. (1996) ∆F508 deletion of 3 bp between 1652-1655 exon 10 57 B1 Kerem et al. (1989) G542X G→T at 1756 exon 11 2 B1 Kerem et al. (1990) R553X C→T at 1789 exon 11 1 A4 Cutting et al. (1990) L568F G→T at 1836 exon 12 1 B3 This study 2184insA insertion of A at 2184 exon 13 1 D3 Dörk et al. (1994b) 2789+5 G→A G→A at 2789+5 intron 14b 4 D3 Highsmith et al. (1997) R933S A→T at 2931 exon 15 1 n.p. Login to comment 87 ABCC7 p.Asp979Ala ABCC7 p.Val938Gly ABCC7 p.Leu973Phe This study V938G T→G at 2945 exon 15 3 D3 This study L973F T→A at 3048 and C→T at 3049 exon 16 1 D3 This study D979A A→C at 3068 exon 16 1 n.p. Login to comment 88 ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys ABCC7 p.Asp1152His ABCC7 p.Leu997Phe ABCC7 p.Val1153Glu ABCC7 p.Tyr1032Cys ABCC7 p.Lys1351Glu ABCC7 p.Leu1388Gln ABCC7 p.Asp1377His This study L997F G→C at 3123 exon 17a 1 A2 Fanen et al. (1992) Y1032C A→G at 3227 exon 17a 1 B3 This study 3272-26 A→G A→G at 3272-26 intron 17a 2 D3 Fanen et al. (1992) D1152H G→C at 3586 exon 18 3 C2, A2 Highsmith et al. (pers. comm.) V1153E T→A at 3590 exon 18 1 B3 This study 3659delC deletion of C at 3659 exon 19 1 C2 Kerem et al. (1990) W1282X G→A at 3978 exon 20 1 D3 Vidaud et al. (1991) N1303K C→G at 4041 exon 21 1 B1 Osborne et al. (1991) K1351E A→G at 4183 exon 22 1 A2 This study D1377H G→C at 4261 exon 22 1 C1 Costes et al. (1995) L1388Q T→A at 4295 exon 23 1 n.p. Login to comment 89 ABCC7 p.Ser1235Arg ABCC7 p.Phe508Cys ABCC7 p.Thr351Ser This study Variants: R75Qg G→A at 356 exon 3 2 A2 Zielenski et al. (1991b) T351S C→G at 1184 exon 7 1 C4 Mercier et al. (1993) 5Th reduction of oligoT tract to 5T at 1342-12 intron 8 26 C2, A4, D3, A2 Chu et al. (1991) F508C T→G at 1655 exon 10 3 C2 Kobayashi et al. (1990) 1716 G→A G→A at 1716 exon 10 3 D3 Kerem et al. (1990) G576Ai G→C at 1859 exon 12 2 D3 Fanen et al. (1992) R668Ci C→T at 2134 exon 13 2 D3 Fanen et al. (1992) S1235R T→G at 3837 exon 19 1 n.p. Cuppens et al. (1993) Q1352Hh G→C at 4188 exon 22 2 C2 Nukiwa and Seyama (pers. comm.) a The nomenclature of mutations follows Beaudet and Tsui (1993) The symbol "̃" is used to designate an amino-acid insertion b Nucleotides are numbered according to the cDNA sequence of Riordan et al. (1989) c Exons and introns are numbered according to Zielenski et al. (1991a) d Allele frequency is given as number of chromosomes e Haplotypes were defined as listed in B below. Login to comment 90 ABCC7 p.Asp1152His ABCC7 p.Met265Arg Minor haplotypes are shown in italics; (n.p.) phase unknown f Personal communications to the Cystic Fibrosis Genetic Analysis Consortium (http://www.genet.sickkids.on.ca/cftr.html): M265R by M. Schwarz, A. Haworth and G. Malone, D1152H by W. E. Highsmith jr., L. Burch, K. J. Friedman, B. M. Wood, A. Spock, L. M. Silverman and M. Login to comment 91 ABCC7 p.Arg75Gln ABCC7 p.Arg668Cys ABCC7 p.Gly576Ala ABCC7 p.Gln1352His ABCC7 p.Gln1352His ABCC7 p.Arg297Trp ABCC7 p.Arg933Ser R. Knowles, Q1352H by T. Nukiwa and K. Seyama are indicated g Missense substitutions R933S and R75Q occurred together in a ∆F508 heterozygous patient h Q1352H is associated with 5T and R297W, respectively i Missense substiutions G576A and R668C are linked on the same allele in both CBAVD patients sence of the vas deferens (CUAVD) and one heterozygote with CBAVD. Login to comment 92 ABCC7 p.Val938Gly The homozygous case may classify V938G as the first "pure" CUAVD mutation, whereas the heterozygous CBAVD patient carries a potentially severe mutation, the new frameshift deletion 174delA, on the other chromosome. Login to comment 93 ABCC7 p.Leu973Phe The amino-acid substitution L973F results from a tandem nucleotide substitution in exon 16; this gives rise to a silent change in codon 972 and to the phenylalanine for leucine substitution at codon 973. Login to comment 94 ABCC7 p.Tyr1032Cys ABCC7 p.Tyr1032Cys Mutation Y1032C is an amino-acid substitution encoded by exon 17a and is predicted to reside within the tenth transmembrane helix of CFTR; it was found in a German CBAVD patient heterozygous for Y1032C and for ∆F508. Login to comment 95 ABCC7 p.Asp979Ala ABCC7 p.Asp1152His ABCC7 p.Ile980Lys ABCC7 p.Val1153Glu D979A and V1153E are non-conservative amino-acid changes in exons 16 and 18, respectively, at positions adjacent to other known CBAVD mutations, viz. I980K and D1152H (Bienvenu et al. 1996; W. E. Highsmith et al. personal communication). Login to comment 96 ABCC7 p.Leu568Phe ABCC7 p.Lys1351Glu ABCC7 p.Leu1388Gln Three other new missense substitutions, viz. L568F, K1351E and L1388Q, are located within or flanking the CFTR nucleotide-binding domains (NBD). Login to comment 97 ABCC7 p.Leu568Phe L568F was detected in a CBAVD male of Turkish descent. Login to comment 99 ABCC7 p.Lys1351Glu K1351E is located at a consensus motif of NBD2, which is essential for the signature of ATP-binding cassette transporters and which is thus a frequent site of CF mutations. Login to comment 100 ABCC7 p.Gly551Asp ABCC7 p.Gly1349Asp ABCC7 p.Lys1351Glu Our finding of a German CBAVD patient heterozygous for ∆F508 and K1351E adds evidence to previous indications that ABC signature mutations have less severe consequences in the second than in the first CFTR nucleotide-binding fold (e.g. the CF mutation pair G551D/ G1349D). Login to comment 101 ABCC7 p.Leu1388Gln ABCC7 p.Leu1388Gln Missense mutation L1388Q flanks NBD2 at its carboxyterminal side and was found in a CBAVD male heterozygous for ∆F508 and L1388Q. Login to comment 109 ABCC7 p.Phe508Cys Splicing variants, such as "5T" or 1716 G→A, and missense variants, such as F508C or the 369 Table 1B Dimorphic marker haplotypes. Login to comment 113 ABCC7 p.Arg75Gln ABCC7 p.Arg668Cys ABCC7 p.Gly576Ala ABCC7 p.Arg933Ser The membrane topology of the CFTR protein was adapted from the original report and has been confirmed in vitro by glycosylation site mutagenesis (Riordan et al. 1989; Chang et al. 1994) double mutant allele G576A and R668C, have previously been reported to be benign but no other mutation could be detected on these alleles in our patients after scanning the whole coding region, except for one case where the R75Q and R933S mutations were found together in a ∆F508 heterozygote. Login to comment 118 ABCC7 p.Arg75Gln The next two most frequent variants were the splice site substitution 1716 G→A and missense substitution R75Q. Login to comment 121 ABCC7 p.Gly551Asp However, no specific association with CAVD was found in the present data set and we observed two proven fathers with the compound heterozygous genotypes ∆F508/1716 G→A or G551D/1716 G→A, respectively, in our cohort of CF families. Login to comment 126 ABCC7 p.Arg75Gln R75Q is a candidate mutation but there is no evidence of a specific association with CAVD. Login to comment 127 ABCC7 p.Arg75Gln ABCC7 p.Arg75Gln We have identified, in a set of 65 CF families, two proven fathers with the compound heterozygous genotype ∆F508/R75Q and additional mutations have been detected here and elsewhere in patients with R75Q alleles (Zielenski and Tsui 1995; D. Hughes, personal communication). Login to comment 128 ABCC7 p.Arg75Gln However, these complex alleles do not explain all cases and a final classification of R75Q requires further examination. Login to comment 129 ABCC7 p.Phe508Cys ABCC7 p.Phe508Cys The less frequent F508C variant was initially reported to be benign (Kobayashi et al. 1990) but is present in three of our CBAVD males who are all compound heterozygous for ∆F508 and F508C with no other detected mutation (one patient has been reported previously by Meschede et al. 1993). Login to comment 130 ABCC7 p.Arg668Cys ABCC7 p.Gly576Ala The missense substitutions G576A and R668C occurred in cis on the same allele in two of our CBAVD males and in three further patients with very mild CF (data not shown); it is thus difficult to decide whether one or both of these changes are required to predispose towards mild disease (Anguiano et al. 1992; Fanen et al. 1992; Chillón et al. 1995). Login to comment 132 ABCC7 p.Gln1352His ABCC7 p.Arg297Trp This male was homozygous for a missense mutation, Q1352H, in exon 22 of the CFTR gene, but heterozygous for a "5T" allele and for the novel R297W missense mutation. Login to comment 133 ABCC7 p.Gln1352His Missense mutation Q1352H, located in the ABC signature of the NBD2 of CFTR, has so far only been observed in the heterozygous state in 1 out of 18 Japanese patients with diffuse panbronchiolitis (K. Seyama, personal communication). Login to comment 134 ABCC7 p.Arg75Gln ABCC7 p.Phe508Cys ABCC7 p.Arg668Cys ABCC7 p.Gly576Ala ABCC7 p.Gln1352His The Q1352H mutation may be insufficient to cause CBAVD but the additional occurrence of one "5T" 370 Variant Allele frequency n (% of chromosomes) Random donors Non-CF CBAVD CF 125G→C 15/178 (8.5%) n.d. 2/212 (0.9%) 1/1000 (0.1%)a R75Q 4/188 (2.2%) 3/130 (2.1%) 2/212 (0.9%)b 1/1000 (0.1%) 5T 9/186 (4.8%) 2/65 (2.9%) 26/212 (12.3%)c 3/1000 (0.3%) F508C 0/188 n.d. 3/212 (1.4%) 2/1000 (0.2%)d 1716G→A 5/188 (2.6%) 3/212 (1.5%) 3/212 (1.4%) 2/1000 (0.2%)e G576A-R668C 0/188 n.d. 2/212 (0.9%)f 3/1000 (0.3%)f Table 2 Frequency distribution of CFTR variants in different subgroups of individuals. Login to comment 137 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Arg347His ABCC7 p.Arg347His ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Ser1251Asn ABCC7 p.Leu206Trp ABCC7 p.Asp979Ala ABCC7 p.Arg75Gln ABCC7 p.Arg75Gln ABCC7 p.Ser1235Arg ABCC7 p.Ala120Thr ABCC7 p.Asp1152His ABCC7 p.Asp1152His ABCC7 p.Asp1152His ABCC7 p.Leu568Phe ABCC7 p.Arg334Leu ABCC7 p.Phe508Cys ABCC7 p.Phe508Cys ABCC7 p.Arg668Cys ABCC7 p.Arg668Cys ABCC7 p.Arg668Cys ABCC7 p.Arg668Cys ABCC7 p.Gly576Ala ABCC7 p.Gly576Ala ABCC7 p.Gly576Ala ABCC7 p.Leu997Phe ABCC7 p.Val938Gly ABCC7 p.Val938Gly ABCC7 p.Val938Gly ABCC7 p.Arg75* ABCC7 p.Ile336Lys ABCC7 p.Leu375Phe ABCC7 p.Asp110His ABCC7 p.Asp110His ABCC7 p.Asp58Asn ABCC7 p.Val1153Glu ABCC7 p.Tyr1032Cys ABCC7 p.Leu619Ser ABCC7 p.Gln1352His ABCC7 p.Gln1352His ABCC7 p.Gln1352His ABCC7 p.Gln1352His ABCC7 p.Lys1351Glu ABCC7 p.Thr351Ser ABCC7 p.Leu1388Gln ABCC7 p.Met265Arg ABCC7 p.Arg297Trp ABCC7 p.Arg297Trp ABCC7 p.Asp1377His ABCC7 p.Glu56Lys ABCC7 p.Arg933Ser ABCC7 p.Arg933Ser ABCC7 p.Leu973Phe Complex alleles are indicated a One CF allele with R75X and 125G→C b One CBAVD allele with R75Q and R933S c One CBAVD allele with 5T and Q1352H d Two CF alleles with F508C and S1251N e One CF allele with 1716G→A and L619S f G576A and R668C were linked on two CBAVD and three CF alleles, whereas two additional CF alleles carried R668C together with the 3849+10kB C→T mutation (Dörk and Stuhrmann 1995) 371 Table 3 CFTR mutation genotypes in 106 males with CAVD Genotype PolyT Frequency Ethnic descent Diagnosis ∆F508/R117H 9/7 21 German, Austrian 20 CBAVD, 1 CUAVD ∆F508/5T 9/5 9 German, Austrian 8 CBAVD, 1 CUAVD ∆F508/F508C 9/7 3 German CBAVD ∆F508/R347H 9/9 2 German CBAVD ∆F508/1716 G→A 9/7 2 German CBAVD ∆F508/3272-26 A→G 9/7 2 German CBAVD ∆F508/E56K 9/7 1 German CBAVD ∆F508/M265R 9/7 1 German-Portuguese CBAVD ∆F508/R334W 9/9 1 German CBAVD ∆F508/T351S 9/9 1 German CBAVD ∆F508/L375F 9/7 1 Volga German CBAVD ∆F508/G576A & R668C 9/7 1 German CBAVD ∆F508/R933S 9/7 1 German CBAVD ∆F508/L997F 9/9 1 German CBAVD ∆F508/Y1032C 9/7 1 German CBAVD ∆F508/D1152H 9/7 1 German CBAVD ∆F508/K1351E 9/7 1 German CBAVD ∆F508/D1377H 9/7 1 Portuguese CBAVD ∆F508/L1388Q 9/7 1 German CBAVD ∆F508/unknown 9/7 4 German 3 CBAVD, 1 CUAVD 5T/5T 5/5 2 German CBAVD 5T/G542X 5/9 2 German, Turkish CBAVD 5T/D58N 5/7 1 Lebanese CBAVD 5T/̃L138 5/7 1 German-Polish CBAVD 5T/1078delT 5/7 1 German CBAVD 5T/R553X 5/7 1 German CBAVD 5T/2184insA 5/7 1 Turkish CBAVD 5T/D979A 5/7 1 Vietnamese CBAVD 5T/D1152H 5/7 1 Turkish CBAVD 5T/3659delC 5/7 1 German CBAVD 5T/S1235R 5/7 1 Greek CBAVD 5T/W1282X 5/7 1 German CBAVD 5T & Q1352H/ R297W & Q1352H 5/7 1 Vietnamese CBAVD 5T/unknown 5/7 1 German CBAVD R117H/L206W 7/9 1 German CBAVD R117H/2789+5 G→A 7/7 1 German CBAVD R117H/unknown 7/7 1 German CBAVD 2789+5 G→A/2789+5 G→A 7/7 1 Lebanese CBAVD 2789+5 G→A/L973F 7/7 1 German CBAVD V938G/V938G 7/7 1 Greek CBAVD V938G/174delA 7/7 1 German CBAVD D110H/D110H 7/7 1 Turkish CBAVD R334L/I336K 7/7 1 German CBAVD R347H/N1303K 9/9 1 German CBAVD L568F/D1152H 7/7 1 Turkish CBAVD 3272-26 A→G/V1153E 7/7 1 German CBAVD R75Q/unknown 7/7 1 German CBAVD A120T/unknown 9/7 1 German CBAVD 1716G→A/unknown 7/7 1 German CBAVD G576A & R668C/unknown 7/7 1 German CBAVD 2752-15 C→G/unknown 7/7 1 Iranian CBAVD Unknown/unknown 17 German, Turkish 7 CBAVD and 1 CUAVD without observed renal agenesis, 9 CBAVD with renal agenesis allele and the R297W mutation on a homozygous Q1352H background may then reduce CFTR function to a disease-causing level. Login to comment 144 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg334Trp ABCC7 p.Arg347His ABCC7 p.Phe508Cys ABCC7 p.Tyr1032Cys ABCC7 p.Met265Arg ABCC7 p.Glu56Lys Lung function tests indicated initial pulmonary deterioration in a few cases (FEV1 forced expiratory volume in 1 s, given as percent predicted) Subject Age Genotype Height Weight Sweat C1- Symptoms (years) (cm) (kg) (mM) 1 33 ∆F508/R117H 172 75 46 Dyspnoe 2 37 ∆F508/R117H 178 83 31 Nasal polyposis 3 31 ∆F508/R117H 181 91 n.d. Nasal polyposis 4 32 R117H/unknown 164 70 33 Recurrent infections 5 33 ∆F508/E56K 193 100 85 Sinusitis, recurrent bronchitis 6 31 ∆F508/M265R 192 112 59 Recurrent infections, pancreatitis 7 33 ∆F508/R334W 182 78 n.d. Recurrent infections, pneumonia 8 28 ∆F508/R347H n.d. n.d. n.d. Recurrent infections 9 32 ∆F508/F508C 192 98 32 Pneumonia 10 34 ∆F508/Y1032C n.d. n.d. n.d. Recurrent bronchitis 11 33 ∆F508/3272-26 A→G 172 82 125 Recurrent infections, maldigestion, FEVI 73% 12 28 ∆F508/unknown 185 95 n.d. Login to comment 145 ABCC7 p.Trp1282* ABCC7 p.Arg347His ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Asp979Ala ABCC7 p.Asp1152His ABCC7 p.Arg334Leu ABCC7 p.Val938Gly ABCC7 p.Val938Gly ABCC7 p.Val938Gly ABCC7 p.Ile336Lys ABCC7 p.Asp110His ABCC7 p.Asp110His ABCC7 p.Asp58Asn Maldigestion 13 25 5T/D58N 184 99 55 - 14 34 5T/̃L138 177 80 53 - 15 33 5T/1078delT 187 87 56 Recurrent bronchitis 16 31 5T/G542X 181 85 79 - 17 31 5T/2184insA n.d. n.d. 60 Borderline pancreatic sufficiency 18 31 5T/D979A n.d. n.d. 55 Recurrent infections, FEVI 76% 19 29 5T/D1152H n.d. n.d. 57 - 20 32 5T/W1282X 180 76 n.d. Recurrent infections, nasal polyposis 21 37 5T/unknown 180 74 n.d. Nasal polyposis 22 28 D110H/D110H 175 80 n.d Asthma bronchiale, obstipation 23 33 R334L/I336K 170 65 n.d. Recurrent infections, nasal polyposis, maldigestion, salt depletion episodes 24 35 N1303K/R347H 167 77 93 - 25 30 V938G/174delA n.d. n.d. 42 - 26 29 V938G/V938G 197 115 n.d. Asthma bronchiale Fig.2 Spectrum of CFTR mutation genotypes in CF patients (left) and in patients with congenital absence of the vas deferens (right). Login to comment 148 ABCC7 p.Asp110His Whereas none of the males with isolated CAVD was homozygous for ∆F508, homozygosity was observed for four other mutations: one Lebanese and one Turkish male with CBAVD were homozygous for the mutations D110H and 2789+5 G→A, respectively, both of which had previously been identified as very mild CF mutations (Dean et al. 1990; Highsmith et al. 1997). Login to comment 149 ABCC7 p.Val938Gly As mentioned above, one further male presenting with unilateral absence of the vas deferens as the only clinical symptom was found to be homozygous for missense mutation V938G. Login to comment 152 ABCC7 p.Arg117His By far the most frequent CAVD genotype in our population was the ∆F508/R117H genotype that was present in every fifth German male presenting with CBAVD. Login to comment 153 ABCC7 p.Arg334Trp ABCC7 p.Arg347His ABCC7 p.Asp1152His A few other genotypes overlapped with those previously observed in some CF adults with mild or very mild disease, e.g. compound heterozygosity for ∆F508 and mutations R334W, R347H, 3272-26 A→G or D1152H. Login to comment 175 ABCC7 p.Val938Gly A cluster of four novel missense substitutions, including the "ultramild" V938G mutation, target the third intracytoplasmic loop. Login to comment 177 ABCC7 p.Arg117His ABCC7 p.Arg347His Two further CAVD missense mutations, viz. R117H and R347H, have been thoroughly studied in vitro and both were shown to result in a pH-sensitive decrease of chloride conductance (Sheppard et al. 1993; Tabcharani et al. 1993). Login to comment 186 ABCC7 p.Arg117His Severe disease results when additional mild mutations such as R117H occur in cis on a "5T" allele in certain populations (Kiesewetter et al. 1993) and the joint effect of both mutations strongly supports the view of CBAVD as representing a partial form of CF. Login to comment 188 ABCC7 p.Arg668Cys ABCC7 p.Gly576Ala The two linked missense substitutions G576A and R668C, for example, have previously been classified as polymorphisms on normal chromosomes (Fanen et al. 1992), as polymorphisms on CBAVD alleles (Osborne et al. 1993; Culard et al. 1994) or as separate disease-causing mutations in CBAVD (Anguiano et al. 1992; Chillón et al. 1995; Mercier et al. 1995). Login to comment 191 ABCC7 p.Phe508Cys ABCC7 p.Gly576Ala Therefore, missense variants, such as F508C or G576A, or splicing variants, such as 1716 G→A, deserve closer examination with regard to what extent they can impair CFTR function in an epithelial tissue, such as the vas deferens. Login to comment 195 ABCC7 p.Arg117His ABCC7 p.Asp1152His Previous studies have reported few homozygous CBAVD patients for mutations R117H, D1152H and "5T" (Costes et al. 1995; Rave-Harel et al. 1995; Zielenski et al. 1995). Login to comment 196 ABCC7 p.Val938Gly ABCC7 p.Asp110His Our analysis adds mutations D110H, 2789+5 G→A and V938G to the growing list of CFTR mutations that, in the homozygous state, can result in a restricted and primarily genital expression of disease. Login to comment 202 ABCC7 p.Arg117His ABCC7 p.Asp1152His Thus, there seem to be two classes of mild CFTR mutations in males: those that primarily target the male genital tract (e.g. R117H, "5T", D1152H) and those that may leave the vas deferens patent but exert deleterious effects at a more advanced age and lead to late-onset disease of the pulmonary tract, as is often observed for the 3849+10kb C→T mutation. Login to comment