Media

Mutation causing one type of male infertility found

20 July 2009 

A genetic mutation that lies behind one type of male infertility has been discovered by researchers at Oxford University, Ghent University in Belgium, and the University of Massachusetts, Amherst in the USA.

The discovery, published in the journal Human Reproduction, may provide a new approach to help some couples that have been unsuccessful in IVF treatments, and could potentially lead to the development of a male contraceptive pill.The mutation was found in a man known to have a defect in his sperm following initially unsuccessful IVF treatment at a clinic at Ghent University Hospital.

The mutation lies in one specific protein present in sperm called PLC zeta. Recent research, in which the Oxford team also played a significant role, has shown that sperm transfers PLC zeta to the egg on fertilisation. The protein initiates a process called ‘egg activation’ which sets off all the biological processes necessary for development of the embryo.

‘An egg cell before fertilisation is in a state of suspended animation. All the biological processes that occur in the growth and development of an embryo are on pause,’ explains Dr John Parrington of the Department of Pharmacology at the University of Oxford. ‘At the moment of fertilisation, when a sperm fuses with the egg, the egg bursts into life. It’s like a Prince waking Sleeping Beauty.

’The research team, funded by the Medical Research Council and Belgian funding agencies, looked at sperm samples from nine men at the same clinic where an IVF procedure known as intracytoplasmic sperm injection, or ICSI, had been unsuccessful. In each of these cases, the eggs had failed to activate. ISCI involves the direct injection of the sperm into the egg, and is often used in IVF treatment to help ensure fertilisation. However, in two to three per cent of cases where ICSI is used, egg activation doesn’t occur and the fertilised egg doesn’t develop.

ICSI was used in 47% of all IVF treatments in the UK in 2006, or over 20,800 cases. So potentially around 600 couples a year in this country could find that they can’t have children in this way.

The scientists conducted a series of experiments to test how well the protein PLC zeta in these samples was functioning. They found that one man had a mutation in the gene for PLC zeta. The mutation was at a critical point and produced a mutant form of the protein that could no longer trigger egg activation. This is the first genetic mutation discovered to explain this type of male infertility.

Other samples showed other problems in PLC zeta: there was not enough protein, it was located in the wrong part of the sperm cell, or a truncated version was produced.

‘We have found that some men are infertile because their sperm fail to activate eggs,’ says Dr Kevin Coward of the Nuffield Department of Obstetrics and Gynaecology at Oxford University, who was also involved in the research. ‘Even though the sperm fuses with the egg, nothing happens. The sperm lack a proper functioning version of the PLC zeta protein involved.’

The Oxford and Ghent University researchers have also demonstrated that it should be possible to overcome this problem. For those couples that need it, providing a working version of the PLC zeta protein in IVF/ICSI treatment should offer them the chance to conceive.The researchers found that mouse egg cells injected with a correct version of the gene for PLC zeta produce the protein for themselves, rather than relying on the sperm cell, and are successfully activated.

‘This was a lab experiment and our method could not be used in a fertility clinic in exactly the same way,’ cautions Dr Parrington. ‘But in the future, if we could produce the PLC protein artificially, we could stimulate egg activation in a completely natural way. For those couples going through IVF treatment where ICSI has failed, it could give them the chance of a baby.

'Since PLC zeta has been shown to be crucial for a fertilised egg to develop into an embryo, a drug that inhibits the protein would be a good candidate for a male contraceptive.

‘It’s a bit of a cliché in the field that every advance like this gets talked up as a possible new contraceptive pill for men,’ says Dr Parrington. ‘However, now we know that this one protein is absolutely critical at the point where life begins, we can think about finding drugs that stop this protein acting, while leaving all the other PLC proteins in the body unaffected. While this discovery is just an initial step and there is no guarantee of success, a targeted male pill that would not have any of the side effects of the female pill is a tantalising prospect.

’An image showing the location of the PLC zeta protein in a sperm cell is available by contacting the Press Office, University of Oxford, on +44 (0)1865 280530 or press.office@admin.ox.ac.uk

For more information please contact the Press Office, University of Oxford, on +44 (0)1865 280530 or press.office@admin.ox.ac.uk. 

Notes to Editors

  •  ‘Reduced amounts and abnormal forms of phospholipase C zeta in spermatozoa from infertile men’ by E Heytens and colleagues (doi10.1093/humrep/dep228) is published online in the journal Human Reproduction.
  • The protein PLC zeta is present in sperm cells and is transferred to the egg on fertilisation. Once in the egg, PLC zeta initiates the release of waves of calcium ions. The fertilised egg uses these waves of calcium to coordinate its growth and development. 
  • Currently, when ICSI has been unsuccessful because egg activation doesn’t occur, it is possible to use a chemical agent that floods the fertilised egg with calcium and kick-starts development of the embryo. This has successfully resulted in some IVF babies (for example, the man in which this mutation was discovered has since gone on to have children), but the method does not replicate the waves of calcium seen in normal egg activation. Introducing a properly functioning PLC zeta protein artificially does result in the waves of calcium that are desired.
  • The research was funded by the Medical Research Council, the Flemish Foundation of Scientific Research, Ghent University and a Belgian Interuniversity Attraction Poles Program grant.
  • Oxford University’s Medical Sciences Division is one of the largest biomedical research centres in Europe. It represents almost one-third of Oxford University’s income and expenditure, and two-thirds of its external research income. Oxford’s world-renowned global health programme is a leader in the fight against infectious diseases (such as malaria, HIV/AIDS, tuberculosis and avian flu) and other prevalent diseases (such as cancer, stroke, heart disease and diabetes). Key to its success is a long-standing network of dedicated Wellcome Trust-funded research units in Asia (Thailand, Laos and Vietnam) and Kenya, and work at the MRC Unit in The Gambia. Long-term studies of patients around the world are supported by basic science at Oxford and have led to many exciting developments, including potential vaccines for tuberculosis, malaria and HIV, which are in clinical trials.