School of Medicine

Infertility research makes spotlight section of the Biochemical Journal

Recent research from Cardiff University utililsing CBS facilities has been published in the Biochemical Journal (BJ).  The importance of this research has been emphasised by it's inclusion in the spotlight section of the BJ website. 

Point mutation disrupts sperm protein activity

Phospholipase C zeta (PLC-zeta) is a sperm specific protein which triggers the initial signalling events in the egg which are required for successful fertilisation.  A mutation in this protein, identified in a patient following failed IVF treatment, was investigated by introducing the equivalent mutation into mouse PLC-zeta.  Mouse eggs were microinjected with mutant PLC-zeta mRNA, which failed to induce the calcium signalling seen with normal PLC-zeta mRNA.  

PLC-zeta works by hydrolysing PIP₂ to IP₃

IP₃ activates the release of calcium from intracellular stores, producing characteristic calcium oscillations in the egg.  Mutant and wild type PLC-zeta protein was produced in bacteria and purified with help from the CBS protein production facility.  These proteins were then used for biochemical testing.  It was found that while the wild type protein did indeed cleave PIP₂ to IP₃, the mutant was incapable of catalysing this reaction. These experiments prove that a single point mutation in the catalytic Y-domain of PLC-zeta is enough to inactivate catalytic activity, resulting in male infertility. 

Recombinant human PLC-zeta may be used to cure some forms of infertility

One future avenue of research is the use of recombinant PLC-zeta in the clinical setting.  Microinjection of PLC-zeta may be able to recover calcium signalling in eggs fused with inactive sperm, offering a real chance of children to otherwise infertile patients.

Reference:

Nomikos M, Elgmati K, Theodoridou M, Calver BL, Cumbes B, Nounesis G, Swann K and Lai FA. (2011) Male infertility-linked point mutation disrupts the Ca2+ oscillation-inducing and PIP(2) hydrolysis activity of sperm PLC-zeta. Biochem. J. 434(2):211-7