Homozygous CCDC146 mutation causes oligoasthenoteratozoospermia in humans and mice

Infertility represents a significant health concern,with sperm quantity and quality being crucial determinants of male fertility.Oligoasthenoteratozoospermia(OAT)is characterized by reduced sperm motility,lower sperm concentration,and morphological abnormalities in sperm heads and flagella.Although variants in several genes have been implicated in OAT,its genetic etiologies and pathogenetic mechanisms remain inadequately understood.In this study,we identified a homozygous nonsense mutation(c.916C>T,p.Arg306*)in the coiled-coil domain containing 146(CCDC146)gene in an infertile male patient with OAT.This mutation resulted in the production of a truncated CCDC146 protein(amino acids 1-305),retaining only two out of five coiled-coil domains.To validate the pathogenicity of the CCDC146 mutation,we generated a mouse model(Ccdc146^(mut/mut))with a similar mutation to that of the patient.Consistently,the Ccdc146mut/mut mice exhibited infertility,characterized by significantly reduced sperm counts,diminished motility,and multiple defects in sperm heads and flagella.Furthermore,the levels of axonemal proteins,including DNAH17,DNAH1,and SPAG6,were significantly reduced in the sperm of Ccdc146^(mut/mut) mice.Additionally,both human and mouse CCDC146 interacted with intraflagellar transport protein 20(IFT20),but this interaction was lost in the mutated versions,leading to the degradation of IFT20.This study identified a novel deleterious homozygous nonsense mutation in CCDC146 that causes male infertility,potentially by disrupting axonemal protein transportation.These findings offer valuable insights for genetic counseling and understanding the mechanisms underlying CCDC146 mutant-associated infertility in human males.

A TOP6BL mutation abolishes meiotic DNA double-strand break formation and causes human infertility

Meiosis is pivotal for sexual reproduction and fertility. Meiotic programmed DNA double-strand breaks(DSBs) initiate homologous recombination, ensuring faithful chromosome segregation and generation of gametes. However, few studies have focused on meiotic DSB formation in human reproduction.Here, we report four infertile siblings born to a consanguineous marriage, with three brothers suffering from non-obstructive azoospermia and one sister suffering from unexplained infertility with normal menstrual cycles and normal ovary sizes with follicular activity. An autosomal recessive mutation in TOP6BL was found co-segregating with infertility in this family. Investigation of one male patient revealed failure in programmed meiotic DSB formation and meiotic arrest prior to pachytene stage of prophase I.Mouse models carrying similar mutations to that in patients recapitulated the spermatogenic abnormalities of the patient. Pathogenicity of the mutation in the female patient was supported by observations in mice that meiotic programmed DSBs failed to form in mutant oocytes and oocyte maturation failure due to absence of meiotic recombination. Our study thus illustrates the phenotypical characteristics and the genotype-phenotype correlations of meiotic DSB formation failure in humans.

Case Study: A Human Pre-Natal Experiment in 1944—“Do No Harm”

Iris du Pré, a professional pianist, wanted a second child, did not conceive quickly and was injected in 1944 by a doctor in Oxford with pregnant mare serum gonadotropin (PMSG). The doctor joked “This child will be a racehorse winner!” In January 1945, Jacqueline du Pré, the remarkable, world-famous cellist was born. In the 1920's and 1930's, animal experimentation and clinical studies had shown that pituitary glycoproteins stimulated the ovary (follicle-stimulating hormone, FSH) and the corpus luteum (luteal-stimulating hormone, LH) which prepared the human womb for embedding a fertilized ovum and that pregnant mare’s blood and urine contained the glycoprotein, PMSG whose origin was placental cells, but surprisingly in humans had the actions of both FSH and LH. However, the PMSG serum alone did not bring about pregnancy. The doctor did not know that without subsequent injection of another factor in correct sequence and timing, PMSG was pointless. In 1947, a placental glycoprotein, found in the 1920's in urine of pregnant women (human chorionic gonadotropin, hCG), when injected in mice subsequent to PMSG, achieved ovulation but not pregnancy. Human application of those findings was extremely risky due to impurities (up to 95%). The Federal Drug Administration (FDA), established in 1938, requested easily bye-passed marketing safety. Companies offered material “sufficiently” purified;professional bodies negated clinical use, tempting to a few. Evidence also suggests that, to sustain pregnancy the doctor also prescribed the new “eostrogen”, diethyl stilbestrol (DES) of negative fame. In 1947, the Nuremberg Code of ethics demanded human experiments by qualified personnel and trials preceded by adequate animal studies. It is not the case here. From five, du Pré had a most exceptional musical memory, almost obsessive musicality and a very difficult school-time socially. Later history: adult masculine build, awkward gait, tendency to recurrent depressions from mid-adolescence, unbalanced thyroidal metabolism, symptoms of numbness in late teens, long breaks for rest from age 25, MS diagnosis at 28 when unable to play, death aged 42. Yet at sixteen and after, she astounded all with technique, passion and unique musical interpretation. Her husband, an outstanding musician: “She had a capacity to imagine sound such as I never met in any other musician”. A close musician colleague: “... it was done before she was born”;perhaps much closer to the truth than realization, for her history it may suggest a fetal neurodevelopment abused in the womb.

Mutations in human Piwi cause male infertility

Subject Code:C05Supported by the National Natural Science Foundation of China,a collaborative study led by Prof.Liu Mofang(刘默芳)from Shanghai Institute of Biochemistry and Cell Biology,Chinese Academy of Sciences and Prof.Shi Huijuan(施惠娟)from Shanghai Institute of Planned Parenthood Research。