• PMID: 28270562
• Gene Name: PLCZ1
• Condition: Male infertility
• Association: Associated
• Mutation: I489F
• Sex: Male
• Infertility type: Male infertility
• Other associated phenotypes: Male infertility

Male infertility-linked point mutation reveals a vital binding role for the C2 domain of sperm PLC?

Nomikos M, Stamatiadis P, Sanders JR, Beck K, Calver BL, Buntwal L, Lofty M, Sideratou Z, Swann K, Lai FA.

Sperm-specific phospholipase C zeta (PLCζ) is widely considered to be the physiological stimulus that evokes intracellular calcium (Ca(2+)) oscillations that are essential for the initiation of egg activation during mammalian fertilisation. A recent genetic study reported a male infertility case that was directly associated with a point mutation in the PLCζ C2 domain, where an isoleucine residue had been substituted with a phenylalanine (I489F). Here, we have analysed the effect of this mutation on the in vivo Ca(2+) oscillation-inducing activity and the in vitro biochemical properties of human PLCζ. Microinjection of cRNA or recombinant protein corresponding to PLCζ(I489F) mutant at physiological concentrations completely failed to cause Ca(2+) oscillations and trigger development. However, this infertile phenotype could be effectively rescued by microinjection of relatively high (non-physiological) amounts of recombinant mutant PLCζ(I489F) protein, leading to Ca(2+) oscillations and egg activation. Our in vitro biochemical analysis suggested that the PLCζ(I489F) mutant displayed similar enzymatic properties, but dramatically reduced binding to PI(3)P and PI(5)P-containing liposomes compared with wild-type PLCζ. Our findings highlight the importance of PLCζ at fertilisation and the vital role of the C2 domain in PLCζ function, possibly due to its novel binding characteristics. CI - © 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society. FAU - Nomikos, Michail AU - Nomikos M AD - College of Medicine, Qatar University, PO Box 2713, Doha, Qatar mixosn@yahoo.com lait@cf.ac.uk. AD - College of Biomedical and Life Sciences, School of Biosciences, Cardiff University, Cardiff, U.K. FAU - Stamatiadis, Panagiotis AU - Stamatiadis P AD - College of Biomedical and Life Sciences, School of Biosciences, Cardiff University, Cardiff, U.K. FAU - Sanders, Jessica R AU - Sanders JR AD - College of Biomedical and Life Sciences, School of Biosciences, Cardiff University, Cardiff, U.K. FAU - Beck, Konrad AU - Beck K AD - College of Biomedical and Life Sciences, School of Dentistry, Cardiff University, Cardiff, U.K. FAU - Calver, Brian L AU - Calver BL AD - College of Biomedical and Life Sciences, School of Biosciences, Cardiff University, Cardiff, U.K. FAU - Buntwal, Luke AU - Buntwal L AD - College of Biomedical and Life Sciences, School of Biosciences, Cardiff University, Cardiff, U.K. FAU - Lofty, Morgan AU - Lofty M AD - College of Biomedical and Life Sciences, School of Biosciences, Cardiff University, Cardiff, U.K. FAU - Sideratou, Zili AU - Sideratou Z AD - National Center for Scientific Research 'Demokritos', 15310 Aghia Paraskevi, Greece. FAU - Swann, Karl AU - Swann K AD - College of Biomedical and Life Sciences, School of Biosciences, Cardiff University, Cardiff, U.K.