About Genetics and Male Infertility

Infertility is defined as the state in which a couple wanting a child is unable to conceive after 12 months of regular intercourse in the absence of contraceptives. ¹ It is a problem faced by couples rather than individuals. ²

Global incidence of infertility is about 13-18%. 1 Male infertility is found to have a role in approximately 50% of infertile couples.³ 

In India, although population growth is a major concern, there are a substantial number of infertile couples. Thus infertility is considered as an important national problem concerning reproductive health.²

Recent advances in assisted reproductive technologies (ART) make it possible for many infertile men with severe male factor infertility to father children. However a significant proportion of infertile males with azoospermia and severe oligozoospermia have a genetic etiology for reproductive failure. ⁴ Thus these technologies raise concerns about passing on genetic abnormalities to the offspring of these men. ⁵ Thus, it is important for the clinicians involved in the treatment of these couples to initiate genetic evaluation and counseling prior to any assisted reproductive procedure

The three most common genetic factors related to male infertility are cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations leading to congenital absence of the vas deferens (CAVD), chromosomal (karyotype) abnormalities and Y-chromosome microdeltions in the azoospermia factor (AZF) locus. ⁴

Infertility can be associated with other far less common genetic conditions. Examples include Kennedy’s disease, Kallman’s syndrome, Prader Willi syndrome, Myotonic dystrophy and Kartagener’s syndrome. ⁶


CFTR gene mutations:

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause congenital bilateral absence of the vas deferens (CBAVD) in approximately 1% of the infertile males. It is a common cause of azoospermia associated with low semen volume and acidic pH. These male will have normal testicular sperm, which are immotile due to the absence of vas deferens. ⁷

Approximately 80% of men with CBAVD are found to have at least one allele mutated in the CFTR gene. 4 The most common CFTR mutation is a three base- paired deletion at position 508 that causes an in-frame deletion of a phenyloalanine. The mutant protein is known as ∆ F508 CFTR. ⁸

Congenital unilateral absence of the vas deferens (CUAVD) is a similar condition that involves aplasia of only one side of the vas deferens. 4 It presents with infertility rarely. CFTR gene mutations have been reported in 43% of men with unilateral absence of the vas deferens. ⁷

Chromosomal abnormalities:

Among men with azoospermia, the frequency of chromosomal abnormalities is estimated to be around 16%. Of these males13% are found to have Klinefelter’s syndrome and the remaining 3% have other chromosomal aberrations, such as ring Y chromosome and translocations. ⁴

5-6% of oligozoospermic men have karyotype anomalies which are mostly autosomal robertsonian and reciprocal translocations. ⁴

In a recent study, sperm from men with extremely severe oligoasthenoteratozoospermia were found to have significantly higher frequency of aneuploidy and diploidy. ⁹

Y- Chromosome microdeletions:

Y chromosome microdeletions are common in about 10-15% of men with azoospermia or severe oligospermia. These microdeletions are too small to be detected by karyotyping. They can be easily identified using polymerase chain reaction. ¹⁰

Most of the microdeletions that cause azoospermia or oligospermia occur in the non-overlapping regions of the long arm of the Y-chromsome. These regions, also called azoospermia factor regions, are responsible for spermatogenesis. The loci are termed AZFa, AZFb and AZFc from proximal to distal Yq (Yq11.21-23 region). Several genes located in AZF regions which are found to be associated with spermatogenesis are viewed as “AZF candidate genes”. ¹⁰

AZFa and candidate genes:

The size of the AZFa region is estimated to be 1Mb. 11 The frequency of deletions in AZFa is lower than that of both AZFb and AZFc. ¹²

The important candidate genes include USP9Y (ubiquitin- specific protease 9, Y chromosome) and DBY (dead box on the Y). ¹⁰

USP9Y is a single copy gene that functions as a C-terminal ubiquitin hydrolase. It is ubiquitously expressed in a wide variety of tissues. ¹⁰

DBY is ubiquitously expressed in humans. In addition it exhibits transcripts unique to the testis. The protein it encodes is an RNA helicase. DBY is more frequently deleted than USP9Y. ¹⁰

The other candidate genes include UTY (ubiquitous TPR motif on the Y) and TB4Y (thymosin B4-isoform). ¹⁰


AZFb and candidate genes:

AZFb locus spans about 1.5 Mb of the Y chromosome. ¹¹

Two important candidate gene families that have been mapped on the AZFb locus are EIF1AY (translation initiation factor 1 A, Y isoform) and RBMY (RNA binding motif on Y). ¹⁰

EIF1AY encodes a ubiquitously expressed translation initiation factor. However it also possesses abundant testis-specific transcripts. ¹⁰

RBMY is a multicopy gene family thought to consist of 30-40 members, some of which are pseudogenes. Numerous RBMY genes have been detected across both arms of the Y chromosome. However, only genes within AZFb, produce detectable levels of the protein. These proteins contain an RNA- binding motif. ¹⁰

AZFc and candidate genes:

AZFc locus spans about 3Mb of the Y chromosome 10.Deletions of the AZFc locus occur more frequently than AZFa or AZFb locus. ¹²

DAZ (deleted in azoospermia) gene is an important candidate gene located in AZFc. This is the most frequently deleted gene in infertile men. ¹³

DAZ belongs to a multicopy gene family. Its autosomal copy is found on short arm of chromosome 3 (DAZ- like). It has 16 exons. It is expressed exclusively in testicular tissue. The protein has a regulatory role in RNA metabolism. ¹⁰

Other genes mapped to the AZFc region include CDY1 (chromodomain Y1) and BPY2 (basic protein Y2). Though the functions of these genes have yet to be elucidated, they are found to be expressed uniquely in the testis. ¹⁰

Other genetic conditions associated with male infertility:

A few rare genetic conditions with which infertility is associated are Kennedy’s disease, Kallman’s syndrome, Prader Willi syndrome, Myotonic dystrophy and Kartagener’s syndrome.

Kennedy’s disease:

Spinobulbar muscular atrophy or Kennedy’s disease is an X linked condition characterized by late onset (at about the age of 30), progressive neurone degeneration, muscular weakness, and male infertility due to testicular atrophy. ¹⁴

The molecular mechanism is the expansion (in excess of 38-40 repeats ) of the trinucleotide repeat sequence (CAG) located in exon 1 of the androgen receptor (AR) gene located on chromosome Xq11-12, which causes an abnormal polyglutamine stretch in the receptor protein. This causes dysfunction of the androgen receptor to the action of circulating androgens. ¹⁴

Kallman’s syndrome:

Hypogonadotropic hypogonadism, anosmia and male infertility are characteristics of Kallman’s syndrome. In most cases the mode of transmission is X linked recessive. However, autosomal dominant or recessive inheritance pattern have also been reported in some families. The gene responsible for the X linked form is on the Xp22.3 (KAL locus). Lack of hypothalamic secretion of gonadotrophin- releasing hormone (GnRH) is the important endocrinological defect. Thus these individuals have very low or undetectable levels of follicle stimulating hormone (FSH), leutinising hormone (LH) and testosterone. ¹⁴

Prader Willi Sydrome:

Hypothalamic deficiency of GnRH is the basic defect of this syndrome. In approximately 75% of the cases the cause is the deletion of region 15q11.13 on the chromosome inherited from the patient’s father. In the remaining 25% of the cases no deletion was identified but both chromosome 15s were inherited from their mother (uniparental disomy). ¹⁴

Myotonic dystrophy:

Myotonic dystrophy is an autosomal dominant trait transmitted with variable penetrance. There is an expansion (more than 35 repeat motifs) of the CTG sequence on the long arm of chromosome 19 (region q13.3). The gene involved encodes for a member of the serine/threonine protein kinase family. 50 to thousands of CTG repeats have been found in mutant alleles. In 30% of individuals with muscular dystrophy, male infertility is observed. Some degree of testicular atrophy occurs in at least 80% of males suffering from this disorder. ¹⁴

Kartagenar syndrome:

Kartagener syndrome (KS) is inherited in an autosomal recessive pattern. Symptoms result from defective cilia motility. Middle ear infections, sinusitis, bronchiectasies, situs inversus and sperm immotility are characteristics of this syndrome. 

The gene responsible has been cloned on the short arm of chromosome 1 (region p35.1). ¹⁴

Conclusion:

Spermatogenesis is a complex genetically controlled process. Disruption of this process causes male infertility. An extensive list of genetic defects is known to be cause the disruption. ¹⁵ A few important genetic defects associated with male infertility were discussed in this review. 

Detection of genetic defects causing infertility in men not only provides a proper diagnosis of the disease, but also has important ethical consequences if the patient is a candidate for assisted reproduction techniques (ART). This is because these patients undergoing ART carry the risk of passing on the genetic abnormalities, which contribute to infertility to their offspring. Thus both genetic counseling and screening are vital before the patient undergoes any assisted reproductive procedure. ⁵

Genetic screening is currently done using techniques such as karyotyping, PCR analysis, and fluorescence in-situ hybridization. As many new spermatogenesis genes are discovered in future, testing mutations will become easier by using DNA chips and microarray technology. ²

References

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