Inheritance of Infertility – Dangers for Generations Downstream?

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Summary

It is apparent that male infertility is associated with mild to moderate expansion of the CAG trinucleotide repeat in the transactivation domain of the androgen receptor gene. Because this expansion may increase in succeeding generations, risking the spinal bulbar atrophy disease known as Kennedy’s disease, further research is warranted to determine the stability of this expansion in infertile men and their offspring conceived by IVF and ICSI.

Introduction

Human infertility can occur as a consequence of historical mutations where the cause of infertility may be an accumulation of defects that finally manifest under the appropriate conditions or be denovo mutations that appear in the genome of the individual without an inheritance from the parental somatic genotype. These latter mutations may occur in the germ cells of parents without being expressed in the remainder of their cells and tissues. Inherited infertility can be either male or female related. Congenital absence of the vas is closely related to cystic fibrosis and may be due to the same mutation. Polycystic ovarian disease also has a genetic component that is inheritable (1) and the deletions in the AZF regions of the Y chromosome are transmitted from father to son (2). Of some interest are the mutations found in the androgen receptor gene that is a nuclear tran scription factor that when activated will induce androgen-regulated genes required for spermatogenesis and sexual differentiation. Mutations will cause androgen insensitivity syndrome and partial syndromes involving female phenotypes and ambiguous genitalia. There are also more subtle effects where no obvious phenotype exists except for reduced fertility that may also involve mutations in the androgen receptor (3).

Point mutations in the ligand binding domain of the androgen receptor can cause a functional defect in the transactivation property of the gene that is expressed in reduced semen quality and infertility (4). Men with severe infertility will usually not transmit gene mutations because they are unlikely to have children by natural methods of conception. The introduction of IVF and particularly intracytoplasmic sperm injection (ICSI) may enable many more mutations associated with infertility to be transmitted to succeeding generations and increase the likelihood of the need to provide assistance to these families for conception in the future. The concern may be increased if these mutations are associated with other pathologies and if the severity of these conditions increases. This may be the case for the trinucleotide (CAG) repeat that codes for a polyglutamine tract in the transactivation domain of the androgen receptor (5).

Association of Trinucleotide Repeat Expansion in the Androgen Receptor Gene with Male Infertility

The androgen modulated DNA binding protein (androgen receptor) is encoded by a single copy gene on the X chromosome (Xq11-12). Hence men are affected by a mutation in the gene and women can be carriers. Besides its well documented role in male sexual differentiation, testicular descent and spermatogenesis, expansion of the CAG repeat in the transactivation causes the spinal and bulbar muscular atrophy disease known as Kennedy’s disease. Normally there are around 20 CAG repeats and expansion to 40 or more will be associated with Kennedy’s disease. Reduced numbers of CAG repeats have been associated with prostate cancer. Interestingly, moderate expansion of the CAG repeat sequence is associated with increasing severity of male infertility.

In a study (5) examining CAG repeat length in infertile and fertile men, where point mutations in the androgen receptor and Y chromosome DAZ and RBM deletions and other explanations for infertility were excluded, showed that men with spermatogenic failure had significantly higher CAG repeat lengths than the fertile controls (mean ± SE; 23.2 ± 0.7 vs 20.5 ± 0.3). Additional data has confirmed this significant difference between infertile and fertile men and also shows that increasing severity of infertility is correlated with increasing CAG repeat length.

Increasing CAG repeat length with increasing severity of male infertility raises the concern that further expansion might increase the possibility of more severe infertility or even Kennedy’s disease in succeeding generations. The continued expansion in trinucleotide repeat length in succeeding generations is characteristic of the trinucleotide repeat diseases and results in earlier and more severe onset of neurological and muscular disorders. This is known as anticipation. The possibility that CAG repeat expansion may occur in children conceived by ICSI because their fathers had moderate expansion needs to be examined. The androgen receptor will be passed to daughters of men treated by ICSI. Examination of the stability of inheritance of these moderate expansions could provide assurance of the safety of ICSI or give warning for the necessity to screen for CAG repeat length in men being treated for infertility by IVF and ICSI.

It is possible that sperm may vary in their CAG repeat length in men with moderate to severe expansion (>40). If this is the case, it would be possible to analyse CAG repeat length in embryos by preimplantation genetic diagnosis (PGD). This strategy could be used to reduce the likelihood of anticipation occurring for families at risk for trinucleotide repeat disorders such as Kennedy’s disease.

References:

References

(1) GHARANI O, WATERWORTH DM, BATTY S, WHILE D, GILLING-SMITH C, CONWAY GS, MCCARTHY M, FRANKS S, WILLIAMSON R. Association of the steroid synthesis gene CYPIIa with polycystic ovary syndrome and hyperandrogenism. Hum Mol Genetics 6: 397-402, 1997.

(2) DE KRETSER DM, MALLIDIS C, MA K, BHASIN. Y chromosome deletions and male infertility. Reprod Med Review 6: 37-53, 1997.

(3) YONG EL, WANG Q, TUT TG, GHADESSY FJ, NG SG. Male infertility and the androgen receptor: molecular, clinical and theraputic aspects. Reprod Med Review 6: 113-131, 1997.

(4) WANG Q, GHADESSY FJ, TROUNSON A, DE KRETSER D, MCLACHLAN R, NG SC, YONG EL. Azoospermia associated with mutation in the ligand-binding domain of the androgen receptor with normal ligand binding, but defective transactivation. J Clin Endocrin Metab 83: 4303-4309, 1998.

(5) DOWSING AT, YONG EL, CLARK M, MCLACHLAN R, DE KRETSER DM, TROUNSON AO. Linkage between male infertility and trinucleotide repeat expansion in the androgen receptor gene. Lancet (in press).