Initially, the researchers screened DNA of 58 men with complete, but unexplained meiotic arrest, which is the interruption of spermatogenesis (the processes by which haploid sperm cells develop from germ cells) and results in altered sperm cell formation. The researchers identified the same homozygous frameshift mutation in M1AP, the gene encoding meiosis 1 associated protein, in three unrelated men.
The team subsequently undertook DNA sequencing of almost 2000 infertile men and identified four patients from Münster, Germany, five members of the same Turkish family, two cases from Portugal and one patient each from Giessen, Germany, Nijmegen, the Netherlands and Newcastle upon Tyne - all with various mutations in the M1AP gene. The common phenotype between all these affected men was the absence of sperm in their semen, known as non-obstructive azoospermia, although occasionally spermatids and rarely a few mature sperm cells were observed in their semen.
The research was conducted over two years, led by Professor Frank Tüttelmann, who set up the working group 'Reproductive Genetics', alongside Dr Margot Wyrwoll and Dr Corinna Friedrich at the Institute of Human Genetics, part of the University of Münster, Germany.
Male infertility affects about seven percent of men, but its causes remain poorly understood. The most severe form of male infertility is azoospermia, in which no sperm is present in the semen. Azoospermia can be divided into obstructive azoospermia with normal spermatogenesis and non-obstructive azoospermia, in which normal spermatogenesis is impaired. Non-obstructive azoospermia can be, in part, caused by meiotic arrest, meaning that no mature sperm will develop. This also means that testicular biopsy and sperm extraction are unlikely to be a viable treatment option in these patients.
Because the genetic evidence linking M1AP to male infertility is strong and mutations in M1AP seem to be a relatively frequent cause of autosomal recessive male infertility, sequencing of the gene may be used in the genetic diagnosis of male infertility.
Professor Tüttelmann explains 'an enhanced understanding for genetic causes for infertility in men, who often have an alleviated sense of guilt, as well as improved genetic counseling, will continue to benefit future treatment. Hence, sequencing of the M1AP gene will be incorporated as part of routine genetic diagnostics immediately.'
The research was published recently in the American Journal of Human Genetics and represents significant progress in furthering our understanding of male infertility.