Male infertility is a complex reproductive disorder that impedes a huge number of couples from having children naturally in the world(Agarwal et al.,2021).As an important pathogenic factor of male infertility,spermato...Male infertility is a complex reproductive disorder that impedes a huge number of couples from having children naturally in the world(Agarwal et al.,2021).As an important pathogenic factor of male infertility,spermatogenic impairments are mainly characterized by impaired male gamete production,reduced sperm quality,or function(Tournaye et al.,2017).Spermatogenesis is a delicate and complex biological process that requires the collaboration of a large number of proteins performing different biological functions(Liu et al.,2021).展开更多
Oligoasthenoteratozoospermia is an important factor affecting male fertility and has been found to be associated with genetic factors.However,there are stll a proportion of oligoasthenoteratozoospermia cases that cann...Oligoasthenoteratozoospermia is an important factor affecting male fertility and has been found to be associated with genetic factors.However,there are stll a proportion of oligoasthenoteratozoospermia cases that cannot be explained by known pathogenic genetic variants.Here,we perform genetic analyses and identify bi-allelic loss-of-function variants of MFSD6L from an oligoasthenoteratozoospermia-affected family.Mfsd6l knock-out male mice also present male subfertility with reduced sperm concentration,motility,and deformed acrosomes.Further mechanistic analyses reveal that MFsD6L,as an acrosome membrane protein,plays an important role in the formation of acrosome by interacting with the inner acrosomal membrane protein SPACA1.Moreover,poor embryonic development is consistently observed after intracytoplasmic sperm injection treatment using spermatozoa from the MFSD6L-deficient man and male mice.Collectively,our findings reveal that MFSD6L is required for the anchoring of sperm acrosome and head shaping.The deficiency of MFsD6L affects male fertility and causes oligoasthenoter-atozoospermia in humans and mice.展开更多
Asthenoteratozoospermia is a common cause of male infertility.To further define the genetic causes underlying asthenoteratozoospermia,we performed whole-exome sequencing in a cohort of Han Chinese men with asthenotera...Asthenoteratozoospermia is a common cause of male infertility.To further define the genetic causes underlying asthenoteratozoospermia,we performed whole-exome sequencing in a cohort of Han Chinese men with asthenoteratozoospermia.Homozygous deleterious variants of MYCBPAP were first identified in two unrelated Chinese cases.Replication analyses in a French cohort revealed an additional asthenoteratozoospermia-affected case harboring a homozygous nonsense variant in MYCBPAP.All of the identified MYCBPAP variants were absent or extremely rare in the public human genome databases.Further functional assays indicated remarkably reduced abundance of MYCBPAP in the spermatozoa from MYCBPAP-associated cases.Subsequently,we generated a Mycbpap knockout(Mycbpap^(−/−))mouse model,which also exhibited male infertility with reduced sperm motility and abnormal morphologies in sperm heads and flagella.Further investigations demonstrated that Mycbpap^(−/−)male mice presented disrupted acrosome biogenesis and abnormally elongated manchette during spermiogenesis.Intriguingly,proteomic analyses indicated that the proteins related to spermatogenesis,acrosomal and flagellar functions were significantly down-regulated in the testes from Mycbpap^(−/−)male mice.Endogenous immunoprecipitation combined with mass spectrometry revealed interactions of MYCBPAP with a ribosome elimination related protein ARMC3 and central apparatus proteins including CFAP65 and CFAP70.Furthermore,MYCBPAP-associated male infertility in humans and mice could be partially overcome by using intracytoplasmic sperm injections.Collectively,these findings illustrate the essential role of MYCBPAP in normal spermatogenesis and homozygous deleterious variants in MYCBPAP can be considered as a genetic diagnostic indicator for infertile men with asthenoteratozoospermia.Our study will provide effective guidance for genetic counseling,clinical diagnosis and assisted reproduction treatments of MYCBPAP-associated male infertility.展开更多
基金supported by the National Key Research and Development Program of China(2021YFC2701400 and 2021YFC2700901)the National Natural Science Foundation of China(32100480,82171607,and 81971441)+4 种基金the Shanghai Municipal Science and Technology Major Project(2017SHZDZX01)the Scientific Research(TP202002)from Anhui Medical Universitythe China Postdoctoral Science Foundation(2020TQ0072)the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2019PT310002)supported by Shanghai Municipal Commission for Science and Technology Grants(19411951800)。
文摘Male infertility is a complex reproductive disorder that impedes a huge number of couples from having children naturally in the world(Agarwal et al.,2021).As an important pathogenic factor of male infertility,spermatogenic impairments are mainly characterized by impaired male gamete production,reduced sperm quality,or function(Tournaye et al.,2017).Spermatogenesis is a delicate and complex biological process that requires the collaboration of a large number of proteins performing different biological functions(Liu et al.,2021).
基金This study was supported by the National Key Research and Development Program of China(2021YFC2701400 and 2023YFC2705600)the National Natural Science Foundation of China(32288101,32100480,32370654,82271639,32322017,and32200485).
文摘Oligoasthenoteratozoospermia is an important factor affecting male fertility and has been found to be associated with genetic factors.However,there are stll a proportion of oligoasthenoteratozoospermia cases that cannot be explained by known pathogenic genetic variants.Here,we perform genetic analyses and identify bi-allelic loss-of-function variants of MFSD6L from an oligoasthenoteratozoospermia-affected family.Mfsd6l knock-out male mice also present male subfertility with reduced sperm concentration,motility,and deformed acrosomes.Further mechanistic analyses reveal that MFsD6L,as an acrosome membrane protein,plays an important role in the formation of acrosome by interacting with the inner acrosomal membrane protein SPACA1.Moreover,poor embryonic development is consistently observed after intracytoplasmic sperm injection treatment using spermatozoa from the MFSD6L-deficient man and male mice.Collectively,our findings reveal that MFSD6L is required for the anchoring of sperm acrosome and head shaping.The deficiency of MFsD6L affects male fertility and causes oligoasthenoter-atozoospermia in humans and mice.
基金supported by the National Natural Science Foundation of China(32288101,32100480,32370654,82271638,32322017)the Innovative Research Team of High-Level Local Universities in Shanghai(SHSMU-ZDCX20212200)+1 种基金Shanghai Hospital Development Center Foundation(SHDC12023121)the outstanding Youth Foundation of Hunan Provincial Natural Science Foundation of China(2023JJ20080).
文摘Asthenoteratozoospermia is a common cause of male infertility.To further define the genetic causes underlying asthenoteratozoospermia,we performed whole-exome sequencing in a cohort of Han Chinese men with asthenoteratozoospermia.Homozygous deleterious variants of MYCBPAP were first identified in two unrelated Chinese cases.Replication analyses in a French cohort revealed an additional asthenoteratozoospermia-affected case harboring a homozygous nonsense variant in MYCBPAP.All of the identified MYCBPAP variants were absent or extremely rare in the public human genome databases.Further functional assays indicated remarkably reduced abundance of MYCBPAP in the spermatozoa from MYCBPAP-associated cases.Subsequently,we generated a Mycbpap knockout(Mycbpap^(−/−))mouse model,which also exhibited male infertility with reduced sperm motility and abnormal morphologies in sperm heads and flagella.Further investigations demonstrated that Mycbpap^(−/−)male mice presented disrupted acrosome biogenesis and abnormally elongated manchette during spermiogenesis.Intriguingly,proteomic analyses indicated that the proteins related to spermatogenesis,acrosomal and flagellar functions were significantly down-regulated in the testes from Mycbpap^(−/−)male mice.Endogenous immunoprecipitation combined with mass spectrometry revealed interactions of MYCBPAP with a ribosome elimination related protein ARMC3 and central apparatus proteins including CFAP65 and CFAP70.Furthermore,MYCBPAP-associated male infertility in humans and mice could be partially overcome by using intracytoplasmic sperm injections.Collectively,these findings illustrate the essential role of MYCBPAP in normal spermatogenesis and homozygous deleterious variants in MYCBPAP can be considered as a genetic diagnostic indicator for infertile men with asthenoteratozoospermia.Our study will provide effective guidance for genetic counseling,clinical diagnosis and assisted reproduction treatments of MYCBPAP-associated male infertility.
