ABCMdb

PMID: 10755189

Stuhrmann M, Dork T
CFTR gene mutations and male infertility.
Andrologia. 2000 Mar;32(2):71-83., [PubMed]

Sentences

No. Mutations Sentence Comment

70 ABCC7 p.Arg117His several publications followed to prove the occur- ground of the R117H mutation and phenotype. Login to comment 72 ABCC7 p.Arg117His CBAVD is, mutation in association with IVS8-5T (see below), in contrast to seven CF patients and all CBAVDin most cases, a genital form of CF, which is either caused by compound heterozygosity for one typical males, where R117H was associated with IVS8-7T (Kiesewetter et al., 1993). Login to comment 75 ABCC7 p.Arg117His Thereby, the mutational spectrum is distinct to typical CF, which is most frequently ported by our own study of 101 CBAVD and five CUAVD males: R117H was exclusively (24 inde-caused by typical (classes 1-3) CF mutations on both alleles (Table 2). Login to comment 76 ABCC7 p.Arg117His pendent alleles) associated with IVS8-7T (Do¨rk et al., 1997).In Germany, DF508/R117H represents the most common CFTR genotype among CBAVD IVS8-5T itself may be the most common atypical CF mutation world-wide (Chillon et al., 1995;patients (Do¨rk et al., 1997; Table 2). Login to comment 77 ABCC7 p.Arg117His Compound heterozygosity for R117H and DF508, or even Zielenski et al., 1995). Login to comment 78 ABCC7 p.Arg117His The length of the polymorphic polypyrimidine tract (five, seven or ninehomozygosity for R117H, in CBAVD patients were also published by others (Bienvenu et al., thymidines) in intron 8 is important for exon 9 splicing efficacy. Login to comment 82 ABCC7 p.Arg117His In contrast, exon 9 ispolypyrimidine tract in the splice acceptor site in intron 8 (IVS8-5T, 7T, 9T; Chu et al., 1993) of present (exon 9+) in 70-100% of CFTR mRNA transcripts from individuals with seven or ninethe CFTR gene in 38 CF patients bearing the genotype DF508/R117H and eight CBAVD males thymidines. Login to comment 83 ABCC7 p.Arg117His World-wide, IVS8-5T is present on approximately 5% of CFTR alleles in the normalcarrying at least one R117H allele and identified a close association between chromosomal back- population (Chu et al., 1993 and Table 2) and on Table 1. Login to comment 84 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Trp1282* ABCC7 p.Trp1282* ABCC7 p.Trp1282* ABCC7 p.Arg347His ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Asp1152His ABCC7 p.Ile1139Val CFTR mutations and male fertility Disorder Number of Proportion of Most frequent mutations (%) patients mutated alleles (%) Ethnic origin Reference CBAVD 17 20.6* DF508 (20.6) French Dumur et al. (1990b) CBAVD 25 38.0 DF508 (26.0) Northern European Anguiano et al. (1992) CBAVD 12 41.7 DF508 (20.8) French Culard et al. (1994) CBAVD 49 45.9 DF508 (32.6), R117H (6.1) Caucasians Oates & Amos (1994) CBAVD 47 21.3 DF508 (8.5), D1152H (3.2) Mostly Askenazim Augarten et al. (1994) CBAVD 30 41.7 DF508 (15.0), G542X (6.7), R117H (3.3) Spanish Casals et al. (1994) CBAVD 67 44.8 DF508 (20.9), R117H (4.5), W1282X (3.7) French Mercier et al. (1995) CBAVD 102 65.7+a DF508 (21.6), 5T (21.1), R347H (2.4) Caucasians Chillon et al. (1995) CBAVD 45 75.6+b DF508 (25.6), 5T (25.6), R117H (3.3), W1282X (3.3) French Costes et al. (1995) CBAVD 25 52.0+c 5T (26.0), DF508 (12.0), R117H (6.0) Caucasian Jarvi et al. (1995) CBAVD 70 68.6+d 5T (25.7), DF508 (19.3), W1282X (7.9) Mostly Caucasian Zielenski et al. (1995) CBAVD 101 79.2+e DF508 (26.2), R117H (11.4), 5T (12.9) Mostly German Do¨rk et al. (1997) CUAVD 10 5.0 DF508 (5.0) Spanish Casals et al. (1995) CUAVD 21 19.0 DF508 (9.5), R117H (4.8) Caucasian Mickle et al. (1995) BEDO 7 78.6 DF508 (28.5), 5T (21.4), R117H (14.3) Mostly German Meschede et al. (1997) IASV 16 3.1 I1139V (3.1) Mostly German Meschede et al. (1997) Azoospermia† 17 23.5+c 5T (14.7), R117H (5.9) DF508 (2.9) Caucasian Jarvi et al. (1995) Azoospermia 21 9.5 DF508 (2.4), G551D (2.4), R117H (2.4), G542X (2.4) Caucasian van der Ven et al. (1996) Spermatogenic failure 18 5.5+c G542X (2.8), 5T (2.8) Caucasian Jarvi et al. (1995) Spermatogenic failure 80 8.7 G542X (4.4), DF508 (3.1) Caucasian van der Ven et al. (1996) Spermatogenic failure 75 2.7+f DF508 (1.3), R117H (0.6), 5T (0.6) Dutch Tuerlings et al. (1998) *Testing only for DF508; +testing included the 5T allele; a-f, frequency of the 5T allele in the general population: a5.2%, n=498; b5.3%, n=131; c,dnot determined; e4.8%, n=186; f3.7%, n=212; †azoospermia with normal vas deferens and bilateral epididymal obstruction. Login to comment 95 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Arg553* ABCC7 p.Arg347Pro ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* Most patients are of German origin CFTR genotype (mutation class in brackets) Patients with typical CF (%) Patients with CBAVD (%) DF508 (2)/DF508 (2) 247 (59.4) 0 DF508 (2)/N1303K (2) 17 (4.1) 0 DF508 (2)/R347P (4) 13 (3.1) 0 DF508 (2)/R553X (1) 11 (2.6) 0 DF508 (2)/G542X (1) 11 (2.6) 0 DF508 (2)/G551D (3) 11 (2.6) 0 DF508 (2)/R1162X (1) 10 (2.4) 0 DF508 (2)/3849+10 KbC T (5) 9 (2.2) 0 DF508 (2)/2789+5G A (5) 9 (2.2) 0 DF508 (2)/3272-26 A G (5) 7 (1.7) 2 (2.6) DF508 (2)/1717-1G A (1) 6 (1.4) 0 DF508 (2)/CFTRdel21Kb (1) 5 (1.2) 0 DF508 (2)/R117H (4) 3 (0.7) 21 (26.9)* DF508 (2)/IVS8-5T (5) 2 (0.5) 9 (11.5)* DF508 (2)/other 33 (7.9) 20 (25.6) Other/other 22 (5.3) 26 (33.3) *Including one CUAVD patient each. Login to comment 116 ABCC7 p.Arg117His ABCC7 p.Arg553* ABCC7 p.Arg347Pro men with BEDO were compound heterozygous Probably the largest molecular genetic study on for DF508 and R117H, two were heterozygous for the etiology of CUAVD was conducted by Mickle DF508, and two were heterozygous for R553X or et al. (1995) who investigated 21 CUAVD males, R347P, respectively. Login to comment 120 ABCC7 p.Ile1139Val The remaining nine ried the rare mutation I1139V, whereas no patients had a non-iatrogenic occlusion of the mutation was detected in the remaining 14 patients contralateral vas at either the inguinal or pelvic (Meschede et al., 1997). Login to comment 122 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Asn1303Lys In this subgroup, eight out of nine patients In summary, CFTR mutations are the molecu- had one of the following mutations detected on lar cause for a variety of different forms of male one of their two CFTR alleles: DF508 (n=4), infertility due to obstructive azoospermia, ranging R117H (n=2), G551D (n=1) and N1303K (n=1) from CBAVD and CUAVD with contralateral (Mickle et al., 1995). Login to comment 125 ABCC7 p.Arg117His ABCC7 p.Val938Gly ABCC7 p.Val938Gly In our own study of five CUAVD males, three had mu- CFTR mutations and spermatogenesis tations on both CFTR alleles (DF508/R117H, Although male infertility in typical or atypical DF508/IVS8-5T, V938G/V938G), one was het- (genital forms of ) CF is primarily due to obstruc- erozygous for DF508, and in only one patient was tion or absence of vas deferens, epididymis and/or no CFTR mutation detected after screening the ejaculatory duct, the question remains as to entire coding region and flanking sequences of the whether mutations in the CFTR gene may also CFTR gene (Do¨rk et al., 1997). Login to comment 134 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Arg117His Five of the patients with obstructive reduced sperm quality and two of 21 men (9.5%) with azoospermia carried one CFTR mutation.azoospermia were heterozygous for IVS8-5T, two were carriers of R117H, and one was heterozygous One azoospermic male was compound heterozygous for G551D and R117H. Login to comment 140 ABCC7 p.Gly542* One further aspect, not discussed by van der Ven et al. (1996), was thatbe caused by CFTR mutations was further substantiated by Meschede et al. (1997) who screened the increase in CFTR mutation frequency in males with reduced sperm quality was almost exclusively affected in a subset of CBAVD patients with CFTR mutations (e.g. IVS8-5T), whereas in other casesdue to the identification of mutation G542X on seven of 160 CFTR alleles (4.3%), which is 20 no disturbances of sperm maturation occur. Login to comment 141 ABCC7 p.Gly542* times higher than the frequency of G542X in the general population of this area (0.2%). Login to comment 142 ABCC7 p.Gly542* G542X is Genotype phenotype correlations particular frequent in Spain and Italy (The Cystic Fibrosis Genetic Analysis Consortium, 1994; The expression of CF disease is highly heterogeneous among different patients. Login to comment 146 ABCC7 p.Gly542* The same mutation G542X was present in one of the 18 often monosymptomatic CF. Login to comment 164 ABCC7 p.Arg117His Germ cell maturation was not decreased in the presence target the male reproductive organs (e.g. R117H, IVS8-5T) and those that may leave the vasof one or two CFTR mutations in the absence of IVS8-5T. Login to comment 188 ABCC7 p.Arg117His PGD is, mainly for ethical and legal reasons, not possible in all European countries (HandysideCFTR mutations R117H and IVS8-5T into the et al., 1992). Login to comment 217 ABCC7 p.Arg117His R117H cystic fibrosis mutation in patients with congenital Chu CS, Trapnell BC, Curristin S, Cutting GR, Crystal RG absence of the vas deferens. Login to comment 239 ABCC7 p.Met348Lys Holsclaw DS, Perlmutter AD, Jockin H, Shwachman H (1971)Deltas CC, Boteva K, Georgiou A, Papageorgiou E, Georgiou Genital abnormalities in male patients with cystic fibrosis.C (1996) Description of a symptomless cystic fibrosis J Urol 106:568-574.L346P/M348K compound heterozygous Cypriot individ- Jarvi K, Zielenski J, Wilschanski M, Durie P, Buckspan M,ual. Login to comment 269 ABCC7 p.Thr338Ile Leoni G, Pitzalis S, Podda R, Zanda M, Silvetti M, Caocci Goshen R, Augarten A, Rahat A, Hurwitz A, Darvasi A, Kerem BS (1997) The molecular basis of partial penetranceL, Cao A, Rosatelli MC (1995) A specific cystic fibrosis mutation (T338I) associated with the phenotype of isolated of splicing mutations in cystic fibrosis. Login to comment