title: A maternally inherited autosomal point mutation in human phospholipase C zeta (PLCζ) leads to male infertility.
abstract: BACKGROUND
  Male factor and idiopathic infertility contribute significantly to global infertility, with abnormal testicular gene expression considered to be a major cause. Certain types of male infertility are caused by failure of the sperm to activate the oocyte, a process normally regulated by calcium oscillations, thought to be induced by a sperm-specific phospholipase C, PLCzeta (PLCζ). Previously, we identified a point mutation in an infertile male resulting in the substitution of histidine for proline at position 398 of the protein sequence (PLCζ(H398P)), leading to abnormal PLCζ function and infertility.
  
  
  RESULTS
  Here, using a combination of direct-sequencing and mini-sequencing of the PLCζ gene from the patient and his family, we report the identification of a second PLCζ mutation in the same patient resulting in a histidine to leucine substitution at position 233 (PLCζ(H233L)), which is predicted to disrupt local protein interactions in a manner similar to PLCζ(H398P) and was shown to exhibit abnormal calcium oscillatory ability following predictive 3D modelling and cRNA injection in mouse oocytes respectively. We show that PLCζ(H233L) and PLCζ(H398P) exist on distinct parental chromosomes, the former inherited from the patient's mother and the latter from his father. Neither mutation was detected utilizing custom-made single-nucleotide polymorphism assays in 100 fertile males and females, or 8 infertile males with characterized oocyte activation deficiency.
  
  
  CONCLUSIONS
  Collectively, our findings provide further evidence regarding the importance of PLCζ at oocyte activation and forms of male infertility where this is deficient. Additionally, we show that the inheritance patterns underlying male infertility are more complex than previously thought and may involve maternal mechanisms.
authors.affiliation: Nuffield Department of Obstetrics and Gynaecology,  Level 3, Women' s Centre, John Radcliffe Hospital, Headington, Oxford OX3 9DU,  UK.
authors.forename: Junaid
authors.initials: J
authors.lastname: Kashir
authors.forename: Michalis
authors.initials: M
authors.lastname: Konstantinidis
authors.forename: Celine
authors.initials: C
authors.lastname: Jones
authors.forename: Bernadette
authors.initials: B
authors.lastname: Lemmon
authors.forename: Hoi Chang
authors.initials: HC
authors.lastname: Lee
authors.forename: Rebecca
authors.initials: R
authors.lastname: Hamer
authors.forename: Bjorn
authors.initials: B
authors.lastname: Heindryckx
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: Deane
authors.forename: Petra
authors.initials: P
authors.lastname: De Sutter
authors.forename: Rafael A
authors.initials: RA
authors.lastname: Fissore
authors.forename: John
authors.initials: J
authors.lastname: Parrington
authors.forename: Dagan
authors.initials: D
authors.lastname: Wells
authors.forename: Kevin
authors.initials: K
authors.lastname: Coward
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007248:Infertility, Male / Q000235:genetics*; D008297:Male; D051379:Mice; D009035:Mothers; D009865:Oocytes / Q000166:cytology; D054801:Phosphoinositide Phospholipase C / Q000235:genetics* / Q000378:metabolism*; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D018075:RNA, Complementary / Q000378:metabolism; D017422:Sequence Analysis, DNA
chemical_list: D018075:RNA, Complementary; C499235:PLCZ1 protein, human; D054801:Phosphoinositide Phospholipase C; D002118:Calcium
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