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Review |
From the * Laboratory for Prenatal Medicine and
Gynecologic Oncology, Women's Hospital/Department of Medicine, University of
Basel, Switzerland; and the Department of
Reproductive Genetics, Reproductive Biomedicine Research Center of Royan
Institute, Tehran, Iran.
| Correspondence to: Dr Ramin Radpour, Laboratory for Prenatal Medicine and Gynecologic Oncolocy, Women's Hospital/Department of Medicine, University of Basel, Switzerland (e-mail: radpourr{at}uhbs.ch). |
| Received for publication February 8, 2008; accepted for publication June 9, 2008. |
A qualitative diagnosis of infertility requires attention to male and
female physical abnormalities including endocrine anomalies and genetic
conditions that interfere with reproduction. Many genes are likely to be
involved in the complex process of reproduction. Congenital bilateral absence
of the vas deferens (CBAVD) is a genital form of cystic fibrosis (CF) that is
responsible for 2%–6% of male infertility. The incidence of CF varies in
different populations; therefore, the incidence of CBAVD will also vary in
different populations. The spectrum and distribution of cystic fibrosis
transmembrane conductance regulator (CFTR) gene mutations differ
between CBAVD and CF patients and are comparable to control individuals.
Combinations of particular alleles at several polymorphic loci yield
insufficient functional CFTR protein. CFTR mutations are also
associated with congenital absence of the uterus and vagina (CAUV). Females
with CF are found to be less fertile than normal healthy women. Because of
techniques such as intracytoplasmic sperm injection (ICSI), CBAVD patients are
now able to father children. Such couples, however, have an increased risk of
having a child with cystic fibrosis, and therefore genetic testing and
counseling should be provided. Around 10% of obstructive azoospermia is
congenital and due to mutations in the CF gene. This review highlights the
relationship of mutations in the CFTR gene with CBAVD and CAUV.
CFTR Gene Mutations and Polymorphisms
The main genetic causes of male infertility are micro-deletions of the Y
chromosome (AZF region) connected with oligospermia or azoospermia, as well as
mutations of the CFTR gene, which is connected with azoospermia and
CBAVD (Dohle et al, 2002).
The CFTR gene contains 27 exons encompassing 
180 kb of DNA on
chromosome band 7q31.2. Several alternatively spliced transcripts have been
found; the most important one lacks exon 9 sequences
(Chu et al, 1993). The CFTR
protein is a glycosylated transmembrane protein that functions as a chloride
channel. CFTR is expressed in epithelial cells of exocrine tissues, such as
the lungs, pancreas, sweat glands, and vas deferens. Apart from its chloride
channel function, CFTR also functions as a regulator of, and is regulated by,
other proteins (Egan et al,
1992).
More than 1500 CF-causing CFTR mutations have been identified (Table; Cystic Fibrosis Genetic Analysis Consortium, 2007). Most mutations are point mutations. A CF patient can either carry an identical CFTR mutation on both CFTR alleles or 2 different CFTR mutations on both CFTR alleles. The distribution of CFTR mutations differs between different ethnic populations (Xu et al, 2007). The most common mutation, F508del, reaches frequencies of about 70% in Northern European populations, while lower frequencies are observed in Southern European populations. Besides F508del, other common mutations exist in most populations, each reaching frequencies of about 1%–2%. Examples include the G542X, G551D, R553X, W1282X, and N1303K mutations. Finally, for a given population, ethnic-specific mutations that reach frequencies of about 1%–2% might exist. For most populations, all these common mutations cover about 85%–95% of all mutant CFTR genes. The remaining group of mutant CFTR genes in a particular population comprises rare mutations, some of them only found in a single family.
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In CBAVD patients having 2 mutant CFTR alleles, at least 1 will be a mild mutation. In CBAVD patients in which a mutation is found on both CFTR genes, about 88% carry 1 severe mutation on 1 CFTR gene and a mild mutation on the second CFTR gene, and about 12% carry mild mutations on both CFTR genes (Claustres et al, 2000). This is in contrast to CF patients, where about 88% of the CF patients carry severe mutations on both CFTR genes, and about 11% carry a severe mutation on one CFTR gene and a mild mutation on their second CFTR gene (Claustres et al, 2000). The most frequent CFTR mutation conferring a mild phenotype found in CBAVD patients is the 5T polymorphism (Chillon et al, 1995). In Caucasians, the 5T polymorphism is found on about 21% of the CFTR genes derived from CBAVD patients, while it is only found on about 5% of the CFTR genes derived from control individuals. 5T is 1 of the alleles found at the polymorphic Tn locus in intron 8 of the CFTR gene. A stretch of 5, 7, or 9 thymidine residues is found at this locus. Less efficient splicing will occur when a lower number of thymidines are found (Figure 1), resulting in CFTR transcripts that lack exon 9 sequences (Chu et al, 1993). Alternatively, spliced CFTR transcripts lacking exon 9 sequences are found in any individual, but the extent varies depending on the alleles present at the Tn locus. In individuals homozygous for a 5T allele, up to 90% of the CFTR transcripts lack exon 9 (Chu et al, 1993). CFTR transcripts lacking exon 9 sequences result in CFTR proteins that do not mature (Delaney et al, 1993; Strong et al, 1993). When 5T is found in compound heterozygosity with a severe CFTR mutation, or even 5T, pathology such as CBAVD might be observed. However, not all males who are compound heterozygous for a severe CFTR mutation and 5T develop CBAVD (eg, some fathers of CF children). The 5T polymorphism was therefore classified as a disease mutation with partial penetrance (Cuppens et al, 1998). Different alleles in this locus can be found depending on the number of TG repeats. The higher number of TG repeats is associated with less efficient exon 9 splicing (Figure 1). The 5T polymorphism can be found in combination with a TG11, TG12, or TG13 allele (11, 12, or 13 TG repeats, respectively). In CBAVD patients, the milder TG11-5T allele is seldom found, while TG12-5T is the most frequently found genotype in CBAVD. The TG13-5T allele is rarer but is also found in CBAVD patients. TG13-5T might even result in pancreatic-sufficient CF, possibly because of additional polymorphisms that affect CFTR, such as V470. In individuals who are compound heterozygous for a severe mutation and the 5T allele, such as fathers of CF patients, 5T is associated with the milder TG11 allele.
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Depending on the effect at the protein level, CFTR mutations can be divided into at least 5 classes (Welsh and Smith, 1993; Wilschanski et al, 1995). Class I mutations result in no CFTR synthesis because of mutations affecting splice sites and nonsense mutations resulting in truncated CFTR protein, which are mostly unstable and therefore degraded, and in mutations shifting the coding frame in the gene (frameshift deletions and insertions). Class II mutations, such as the most common mutation F508del, result in CFTR proteins that fail to mature and are degraded. Class III mutations result in CFTR proteins that mature and therefore reach the apical membrane of the cell but provide abnormal regulatory properties of the chloride channel. Class IV mutations result in CFTR channels with abnormal conductive properties because of mutations in the conductivity pore. Finally, Class V mutations result in some functional CFTR proteins. Class I, II, and III mutations are severe mutations, while class IV and V mutations are known as mild mutations.
CFTR Protein and Molecular Determinants of the Channel Pore
The CFTR molecule is made up of 2 homologous repeats, each containing 6
transmembrane (TM) regions followed by an intracellular nucleotide-binding
domain (NBD; Figure 2). These 2
halves are joined by an intracellular regulatory (R) domain. Recently, a low
resolution crystal structure of CFTR was obtained
(Rosenberg et al, 2004), which
showed membrane-spanning regions lining a central pore, the pathway through
which Cl– ions cross the membrane. However, the identity of
the TM regions forming the pore, or even the number of TMs that line the pore,
cannot be identified in this structure. Nevertheless, homology with the
structures of other ATP-binding cassette (ABC) proteins
(Locher et al, 2002;
Rosenberg et al, 2005)
suggests that the CFTR pore is lined with multiple 
-helical TM regions
in a reasonably parallel fashion. This overall pore architecture is common
with ligand-gated Cl– channels
(Unwin 2003;
Cascio 2004) but is in stark
contrast to the seemingly haphazard arrangement of membrane-associated
-helices observed in Cl– channels
(Dutzler et al, 2002).
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Recently, the relationship between CFTR mutations and the congenital absence of the uterus and vagina (CAUV), which affects 1 in 5000 females, was examined upon the rationale that the embryological development of the müllerian ducts directly depends on the prior normal development of the wolffian ducts (Timmreck et al, 2003). Samples from 25 patients with CAUV were tested for the 33 most common CFTR mutations, including the 5T allele. The data suggested that it is unlikely for CFTR mutations to cause CAUV in females (Timmreck et al, 2003). Finding that CFTR mutations are associated with 80% of cases of CBAVD, a wolffian duct anomaly, but are not associated with CAUV, a müllerian duct anomaly, provides further evidence on the timing of CFTR damage in CBAVD. The effects of the CFTR mutations on the wolffian duct derivatives must occur after the ninth week of embryological development, at a time when the wolffian and müllerian ducts have completely separated and are developing independently.
Genotype-Phenotype Correlations in Cystic Fibrosis
Analyses of the correlation between phenotype and genotype showed that the
CFTR mutations could be grouped into 2 categories, mild or severe,
with respect to pancreatic function
(Kristidis et al, 1992). The
severe mutations are associated with pancreatic insufficiency, whereas the
mild mutations, leading to a higher residual CFTR activity, confer pancreatic
sufficiency (Kristidis et al,
1992). A CF patient is likely to be pancreatic-sufficient if he
has 1 or 2 mild mutations.
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Males With CFTR Mutations (CBAVD Males)
The majority of adult males with CF (99%) have CBAVD. CBAVD is also
encountered in 1%–2% of infertile males without cystic fibrosis
(Blau et al, 2002). Men with
CBAVD but without CF gene mutations have a high incidence of urinary tract
malformations (Dork et al,
1997). The group with urinary tract anomalies represents a
separate clinical entity not related to CF and has different embryological
pathogenesis. Some forms of infertility found in otherwise healthy men have
also been reported to be associated with CFTR mutations, especially
obstructive azoospermic conditions such as CBAVD, CUAVD, or epididymal
obstruction and bilateral ejaculatory duct obstruction with concomitant
seminal vesicle anomalies (Welsh and Smith
et al, 1995). CBAVD is caused by a disruption in the vas deferens,
a wolffian duct derivative. In a widespread study of CBAVD in Iran, including
120 cases of men with CBAVD, the analysis of the entire coding sequences of
CFTR gene allowed us to identify 19 different mutations in Iranian
CBAVD patients (Figure 3).
These mutations have been described previously in Iranian patients with CBAVD
(Radpour et al, 2006a and
2006b). Of those, 5 cases were
homozygous or compound heterozygous (+/+), 67 had only one mutation
(+/–), and 49 cases had neither mutation (–/–;
IVS8-5T was not involved). The result of our study reflects the high
allelic heterogeneity of CFTR gene mutations, although 2 mutations,
IVS8-5T and F508del, were found to be more common in Iranian CBAVD
patients. IVS8-5T was observed with TG12 or TG13 haplotypes on 61
chromosomes, thus confirming the association of this splice site variant with
CBAVD in Iranian patients. Screening for IVS8-5T and F508del together
led to the identification of more than one-third of alleles. All of the
patients with completely resolved mutation genotypes carried a missense or
splicing mutation on at least 1 allele, but in 3 cases we found 1 nonsense
mutation (Radpour et al, 2007,
2008). The diagnosis of CBAVD
is based on the presence of azoospermia in subjects with normal or small size
testes, nonpalpable vas deferens, and the characteristic ultrasonographic view
and changes in the physical and biochemical properties of ejaculate (ie, small
volume, low pH, and low fructose concentration). Genital abnormalities may
occur early in CF but are less commonly diagnosed than in adults. They are
found more often in pancreatic-insufficient than in pancreatic-sufficient CF
patients (Blau et al,
2002).
In up to 20% of the CBAVD patients, absence of the vas deferens is associated with renal malformations. In a small study, this CBAVD etiology was suggested not to be related to CFTR mutations, as no CFTR mutation could be identified in this group of 10 CBAVD patients (Augarten et al, 1994). However, in a more recent study, 2 of 4 CBAVD patients with only 1 kidney were carriers of a CFTR mutation; 1 of them was even compound heterozygous for F508del and 5T (Daudin et al, 2000).
Involvement of CFTR in Forms of Male Infertility Other Than CBAVD
There are reports that CFTR is also involved in forms of
infertility other than CBAVD. In a small study of 17 patients with obstructive
azoospermia in which the vas deferens and/or epididymis was present but
obstructed, a mutation in the CFTR gene was identified in 8 of 34
(23.5%) CFTR genes (Jarvi et al,
1995). It should be noted that 5 of the 8 mutant CFTR
genes carried the 5T allele. In another study, 14 of 80 (17.5%) men
with a variety of diagnoses varying from oligozoospermia to
oligoasthenoteratozoospermia carried a CFTR mutation
(Timmreck et al, 2003).
However, in another report, 75 patients with oligoasthenoteratozoospermia were
studied, and the frequency of CFTR mutations was not significantly
different from the control population
(Tuerlings et al, 1998). The
involvement of CFTR in forms of male infertility other than CBAVD is
thus not clear and needs to be further investigated. Indeed, CFTR is
regulated during the generation of spermatozoa
(Trezise et al, 1993). Here,
CFTR transcripts are confined to postmeiotic round spermatids. During
this development stage, haploid spermatids are converted into spermatozoa.
Nucleus condensation and decrease in cytoplasm volume, which are thought to be
caused by reduction of intracellular water content, occur in this phase.
Maximal CFTR expression precedes this stage. It cannot therefore be
excluded that very mild functional CFTR polymorphisms are still
involved in forms of male infertility other than CBAVD.
Females With CFTR Mutations (CAUV Females)
Females with CF are found to be less fertile than normal healthy women. In
CF females, malnutrition is the main cause of delayed puberty and amenorrhea
(Josserand et al, 2001).
Delayed pubertal increments of serum gonadotrophin and sex steroids suggest
late maturation of the reproductive endocrine system. The patients who were
homozygous for the most common mutation, F508del, and those with pathological
oral glucose tolerance tests were significantly delayed in menarchal age. The
majority of the patients had essential fatty deficiency, which may cause
pubertal delay (Johannesson et al,
1997).
The low fertility in CF females is known to be caused mainly by tenacious impermeable cervical mucus, which does not undergo the typical changes during menstrual cycle because of defective CFTR protein expressed in the cervix (Johannesson et al, 1998). Some CF women do not ovulate. They have higher total serum testosterone concentration and signs of insulin resistance similar to those found in women with polycystic ovarian syndrome. Anovulation due to malnutrition and catabolism has been suggested as a secondary cause of infertility. CF patients might have inflammation in their tissues prior to infection with an imbalance of proinflammatory cytokines versus the anti-inflammatory ones. CFTR might increase acidification of synaptic vesicles, and for that reason, it plays an important role in central regulation of sexual maturation and fertility (Johannesson et al, 1997). Ovulation in these chronically ill women may also be influenced by physiologic and psychologic stress. CFTR mutations are associated with congenital absence of the uterus and vagina as well (CAUV; Timmreck et al, 2003). Since the embryologic development of the müllerian ducts directly depends on the prior normal development of the wolffian ducts, the same gene products may be necessary for normal embryologic development of both ducts' systems.
The incidence of the 33 CFTR mutations found in the patients with CAUV (8%) was twice as high as that found in the general population (4%) but much less than the incidence of CFTR mutations in men with CBAVD (80%). These data suggest that it is unlikely for CFTR mutations to cause CAUV in females in the same way as they cause CBAVD in males. Furthermore, the data suggest that CAUV in females may be the same disorder as CBAVD in males who do not have CFTR mutations. The National Institutes of Health recommends genetic counseling for any couple attempting assisted reproductive techniques when the man has CF or obstructive azoospermia and is positive for a CF mutation (Sokol, 2001). Clinical genetic conditions of a family considering assisted reproduction of infertility can be established by evaluating the full family history and by documenting pregnancy and fetal, neonatal, and pediatric loss of life, as well as by cytogenetic studies of the couple and DNA mutation analysis for cystic fibrosis mutations.
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Risk of CF, CBAVD, or CFTR-opathies for Offspring
For a couple with CBAVD associated with CFTR defects planning to have its
own genetic children, the risk for both male and female offspring of having CF
or related diseases, and for male offspring of having CBAVD, depends on
whether or not the female partner is a carrier, since 1 mutated allele will
always be inherited from the male. As the carrier frequency of CFTR
mutations in many Caucasian populations is in the order of 1/22 to 1/30, it is
highly recommended that genetic testing for CFTR mutations be offered
to the couple prior to ICSI. The genetic counselor should determine whether
there is a family history of CF and determine the couple's ethnicity, as this
will affect their carrier risk. The genetic aspect of CBAVD is more complex
than in CF, since (1) genetic analysis is able to prove but not to exclude the
diagnosis of a genital form of CF, and (2) the risk of CF or CBAVD in the
offspring may be unpredictable when rare mutations are identified in the male
or the female. The couple should be informed that the test cannot detect all
mutations within the gene. Therefore, a negative mutation screen reduces, but
does not eliminate, the risk of being a carrier
(Figure 4).
Acknowledgments
The authors wish to thank Dr Mohamad Ali Sedighi Gilani, Dr Reza Samani, and Mr Kamal Alizadeh for their cooperation on this work and Mrs Regan Geissmann for proofreading the text.
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