Polycystic ovary syndrome(PCOS)is a heterogeneous disorder with evidence of polygenetic components,and obesity may be a risk factor for hyperandrogen ism.Previous studies have shown that LHCGR is en riched in the ovar...Polycystic ovary syndrome(PCOS)is a heterogeneous disorder with evidence of polygenetic components,and obesity may be a risk factor for hyperandrogen ism.Previous studies have shown that LHCGR is en riched in the ovary and LHCGR deficiency causes infertility without typical PCOS phenotypes.ALMS1 is implicated in obesity and hyperandrogenism,the common phenotypes among PCOS patients.Through whole-exome sequencing of 22 PCOS families and targeted candidate gene sequencing of additional 65 sporadic PCOS patients,we identified potential causative mutations in LHCGR and ALMS1 in a sibling-pair PCOS family and three sporadic PCOS patients.The expression of LHCGRL638 P in granulosa-like tumor cell line(KGN)cells promoted cyclic adenosine monophosphate production and granulosa cell proliferation,indicating that LHCGRL638 P is an activating mutation.Lhcgr~(L642 P/L642 P)mice showed an irregular estrous cycle,reduced follicles with dynamic folliculogenesis,and increased testosterone(T),estradiol(E2),and dehydroepiandrosterone.Lhcgr~(+/L642 P)AIms1~(+/PB)mice displayed increased T and E2 but decreased late secondary and preovulatory follicles.We showed that activating mutation of LHCGR likely plays important roles in the pathophysiology of PCOS involving abnormal reproductive physiology,whereas ALMS1 deficiency may promote anovulatory infertility via elevated androgens,suggesting that the disturbed LHCGR and ALMS1 cooperatively induce PCOS phenotypes,characterized as anovulation and hyperandrogenemia frequently observed in PCOS patients with obesity.展开更多
Globally,infertility is a serious health problem affecting about 15%of reproductive age couples according to the data reported by the World Health Organization.Non-obstructive azoospermia(NOA)is acknowledged as one of...Globally,infertility is a serious health problem affecting about 15%of reproductive age couples according to the data reported by the World Health Organization.Non-obstructive azoospermia(NOA)is acknowledged as one of the most serious phenotypes of male infertility.Approximately 1%of the male population and 10%of infertile men were affected by NOA(Xie et al.,2022).As reported,meiotic arrest is one of the major etiologies leading to the NOA.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
Human genetic variants have long been known to play an important role in both Mendelian disorders and common diseases. Notably, pathogenic variants are not limited to single-nucleotide variants. It has become apparent...Human genetic variants have long been known to play an important role in both Mendelian disorders and common diseases. Notably, pathogenic variants are not limited to single-nucleotide variants. It has become apparent that human diseases can also be caused by copy number variations （CNVs）, especially patient- specific novel CNVs （lafrate et al., 2004; Sebat et al., 2004; Redon et al., 2006; LuDski, 2007; Zhan~ et al.. 2009： Wu et al.. 2015）.展开更多
Wnt signaling pathways,including the canonical Wnt/β-catenin pathway,planar cell polarity pathway,and Wnt/Ca2+signaling pathway,play important roles in neural development during embryonic stages.The DVL genes encode ...Wnt signaling pathways,including the canonical Wnt/β-catenin pathway,planar cell polarity pathway,and Wnt/Ca2+signaling pathway,play important roles in neural development during embryonic stages.The DVL genes encode the hub proteins for Wnt signaling pathways.The mutations in DVL2 and DVL3 were identified from patients with neural tube defects(NTDs),but their functions in the pathogenesis of human neural diseases remain elusive.Here,we sequenced the coding regions of three DVL genes in 176 stillborn or miscarried fetuses with NTDs or Dandy-Walker malformation(DWM)and 480 adult controls from a Han Chinese population.Four rare mutations were identified:DVL1 p.R558 H,DVL1 p.R606 C,DVL2 p.R633 W,and DVL3 p.R222 Q.To assess the effect of these mutations on NTDs and DWM,various functional analyses such as luciferase reporter assay,stress fiber formation,and in vivo teratogenic assay were performed.The results showed that the DVL2 p.R633 W mutation destabilized DVL2 protein and upregulated activities for all three Wnt signalings(Wnt/β-catenin signaling,Wnt/planar cell polarity signaling,and Wnt/Ca2+signaling)in mammalian cells.In contrast,DVL1 mutants(DVL1 p.R558 H and DVL1 p.R606 C)decreased canonical Wnt/β-catenin signaling but increased the activity of Wnt/Ca2+signaling,and DVL3 p.R222 Q only decreased the activity of Wnt/Ca2+signaling.We also found that only the DVL2 p.R633 W mutant displayed more severe teratogenicity in zebrafish embryos than wild-type DVL2.Our study demonstrates that these four rare DVL mutations,especially DVL2 p.R633 W,may contribute to human neural diseases such as NTDs and DWM by obstructing Wnt signaling pathways.展开更多
During spermiogenesis,haploid spermatids undergo dramatic morphological changes to form slender sperm flagella and cap-like acrosomes,which are required for successful fertilization.Severe deformities in flagella caus...During spermiogenesis,haploid spermatids undergo dramatic morphological changes to form slender sperm flagella and cap-like acrosomes,which are required for successful fertilization.Severe deformities in flagella cause a male infertility syndrome,multiple morphological abnormalities of the flagella(MMAF),while acrosomal hypoplasia in some cases leads to sub-optimal embryonic developmental potential.However,evidence regarding the occurrence of acrosomal hypoplasia in MMAF is limited.Here,we report the generation of base-edited mice knocked out for coiled-coil domain-containing 38(Ccdc38)via inducing a nonsense mutation and find that the males are infertile.The Ccdc38-KO sperm display acrosomal hypoplasia and typical MMAF phenotypes.We find that the acrosomal membrane is loosely anchored to the nucleus and fibrous sheaths are disorganized in Ccdc38-KO sperm.Further analyses reveal that Ccdc38 knockout causes a decreased level of TEKT3,a protein associated with acrosome biogenesis,in testes and an aberrant distribution of TEKT3 in sperm.We finally show that intracytoplasmic sperm injection overcomes Ccdc38-related infertility.Our study thus reveals a previously unknown role for CCDC38 in acrosome biogenesis and provides additional evidence for the occurrence of acrosomal hypoplasia in MMAF.展开更多
Dear Editor,The most severe type of male infertility,nonobstructive azoospermia(NOA),is characterized by clinical heterogeneity,implying the involvement of different acquired and genetic factors.However,the cause of N...Dear Editor,The most severe type of male infertility,nonobstructive azoospermia(NOA),is characterized by clinical heterogeneity,implying the involvement of different acquired and genetic factors.However,the cause of NOA is unidentified in a substantial number of patients after the exclusion of all-known acquired factors and routine genetic testing,such as karyotype and Y chromosome microdeletion analysis.1 With the recent rapid development of whole-exome sequencing(WES),an increasing number of novel monogenic causes have been identified.Recently,RAD51-associated protein 2(RAD51AP2)was reported to be a novel causative gene of NOA in a monogenic recessive manner in two sporadic patients.2 Here,we studied the WES data for a family with two NOA patients and found that both carried a novel homozygous loss-of-function(LoF)mutation in RAD51AP2.展开更多
Genetic factors play important roles in the etiology of male infertility.The routine clinical genetic testing for human spermatogenic failure is currently limited to abnormal karyotypes(e.g,47,XXY for Klinefelter synd...Genetic factors play important roles in the etiology of male infertility.The routine clinical genetic testing for human spermatogenic failure is currently limited to abnormal karyotypes(e.g,47,XXY for Klinefelter syndrome)and Y chromosomal microdeletions.^(1)However,these chromosomal variants only account for approximately 20%of the infertile males with nonobstructive azoospermia.The vast majority of male infertile cases are genetically unexplained.With the recent advances in genomic technologies,the genome-wide dissections at the nucleotide resolution have been achieved,and the novel genetic factors involved in human male infertility have been continuously uncovered.Furthermore.展开更多
T-box transcription factor T(TBXT;T)is required for mesodermal formation and axial skeletal development.Although it has been extensively studied in various model organisms,human congenital vertebral malformations(CVMs...T-box transcription factor T(TBXT;T)is required for mesodermal formation and axial skeletal development.Although it has been extensively studied in various model organisms,human congenital vertebral malformations(CVMs)involving T are not well established.Here,we report a family with 15 CVM patients distributed across 4 generations.All affected individuals carry a heterozygous mutation,T c.596A>G(p.Q199R),which is not found in unaffected family members,indicating co-segregation of the genotype and phenotype.In vitro assays show that T p.Q199R increases the nucleocytoplasmic ratio and enhances its DNA-binding affinity,but reduces its transcriptional activity compared to the wild-type.To determine the pathogenicity of this mutation in vivo,we generated a Q199R knock-in mouse model that recapitulates the human CVM phenotype.Most heterozygous Q199R mice show subtle kinked or shortened tails,while homozygous mice exhibit tail filaments and severe vertebral deformities.Overall,we show that the Q199R mutation in T causes CVM in humans and mice,providing previously unreported evidence supporting the function of T in the genetic etiology of human CVM.展开更多
Premature ovarian insufficiency(POI)is a severe female reproductive disorder that affects 1%of women in general populations(European Society for Human Reproduction and Embryology[ESHRE]Guideline Group on POI et al.,20...Premature ovarian insufficiency(POI)is a severe female reproductive disorder that affects 1%of women in general populations(European Society for Human Reproduction and Embryology[ESHRE]Guideline Group on POI et al.,2016).An increasing prevalence up to 3.7%has been reported in a recent meta-analysis(Golezar et al.,2019).POl can lead to infertility or subfertility,as well as a range of complex complications suffering multi-organ systems,seriously threatening women's health and reducing the life quality.By contrast,POl is a representative heterogeneous disease with multiple etiologies.While more than 70 causative POI genes have been identified,the etiology of more than half of the POI patients is still ambiguous(Jiao et al.,2018).Unreported POI causative genes,therefore,remain to be identified.展开更多
Huang et al.[1]have put forward reasonable suggestions regarding certain findings of our recently published article,specifically including:(i)the cut-off values and limitations of the Edinburgh Postnatal Depression Sc...Huang et al.[1]have put forward reasonable suggestions regarding certain findings of our recently published article,specifically including:(i)the cut-off values and limitations of the Edinburgh Postnatal Depression Scale(EPDS);(ii)the restriction of data collection in our study to the third trimester;(iii)the sampling methodology employed in this study;(iv)the use of binary versus ternary classification for EPDS scores;(v)the lack of 95%confidence intervals for prevalence estimates;and(vi)the assessment of participants’prior mental health history.As described in this Reply,we interpreted the results of our article by reviewing and referring to other published articles.展开更多
Background While maternal psychological stress during mid-to-late pregnancy has been linked to offspring allergies,the impact of early pregnancy distress remains unclear.This study investigates the association between...Background While maternal psychological stress during mid-to-late pregnancy has been linked to offspring allergies,the impact of early pregnancy distress remains unclear.This study investigates the association between maternal depressive and anxiety symptoms in early pregnancy and allergic diseases in offspring.Methods Based on a birth cohort of 5263 children,antenatal depressive and anxiety symptoms in early pregnancy were assessed via the Patient Health Questionnaire and Generalized Anxiety Disorder Questionnaire,respectively.Allergic outcomes,including asthma,atopic dermatitis(AD),and allergic rhinitis(AR),were evaluated via structured questionnaires.Relative risks(RRs)with 95%confidence intervals(CIs)were estimated via generalized linear models,whereas restricted cubic splines were used to explore linear and non-linear associations between maternal distress and allergic outcomes.Results Maternal depressive symptoms in early pregnancy were associated with an increased risk of AD[adjusted RR(95%CI)=1.15(1.03–1.29)]and AR[1.52(1.29–1.79)].Maternal anxiety symptoms in early pregnancy were associated with increased risks of AD[1.11(1.02–1.21),mild anxiety]and AR[1.33(1.04–1.68),moderate to severe anxiety].Dose‒response analyses revealed graded relationships between distress severity and allergic outcomes.In the joint analysis,comorbid depression and anxiety in early pregnancy were associated with an increased risk of AD[1.15(1.05–1.26)]and AR[1.42(1.23–1.63)].Subgroup analysis revealed a greater risk of asthma for boys born to mothers with mild anxiety[1.95(1.20–3.15)]but not for girls.Conclusion Maternal distress in early pregnancy is associated with an increased risk of allergic diseases in offspring during toddlerhood.展开更多
Antenatal depression is a significant contributor to maternal morbidity in the perinatal period[1].It has also been associated with an increased risk for premature delivery,decreased rates of breastfeeding initiation,...Antenatal depression is a significant contributor to maternal morbidity in the perinatal period[1].It has also been associated with an increased risk for premature delivery,decreased rates of breastfeeding initiation,and a broad range of adverse child out-comes,including emotional problems,externalizing difficulties,attachment issues,and poorer cognitive development[2-6]Depression in the antenatal period may persist postnatally and increase in severity further exacerbating the negative conse-quences.There are considerable geographical differences in ante-natal depression prevalence rates across China,ranging from 9.8%to 35.4%,which is likely due to variations in demographic,lifestyle,social,and economic factors[7,8].Heterogeneity in study design and data source has also resulted in these wide variations.Further,previous Chinese studies examining antenatal depression have been limited due to relatively small sample sizes,short study peri-ods,and a focus on only one specific geographical district.Limited prevalence data in China suggest that a large-scale multi-center study is warranted.展开更多
Prohibitin(PHB),an evoluti on arily con served mitochondrial inner membra ne protein,is highly expressed in cells that require strong mitoch on drial function.Recently,we dem on strated that the deleti on of Phb in sp...Prohibitin(PHB),an evoluti on arily con served mitochondrial inner membra ne protein,is highly expressed in cells that require strong mitoch on drial function.Recently,we dem on strated that the deleti on of Phb in spermatocytes results in impaired mitochondrial function.In addition,PHB expression in the mitochondrial sheath of human sperm has a significantly negative correlation with mitochondrial reactive oxygen species levels,but a positive one with mitochondrial membrane potential and sperm motility.These results suggest that mitochondrial PHB expression plays a role in sperm motility.However,the mechanism of PHB-mediated regulation of sperm motility remai ns unk nown.Here,we dem on strate for the first time that PHB interacts with protei n kinase B(AKT)and exists in a complex with phospho-PHB(pT258)and phospho-AKT in the mitochondrial sheath of murine sperm,as determined using colocalization and coimmunoprecipitation assays.After blocking AKT activity using wortmannin(a phosphatidylinositol 3-kinase[PI3K]inhibitor),murine sperm have significantly(P<0.05)decreased levels of phospho-PHB(pT258)and the total and progressive motility.Furthermore,significantly(P<0.05)lower levels of phospho-PI3K P85 subunit a+γ(pY199 and pY46)and phospho-AKT(pS473;pT308)are found in sperm from infertile asthenospermic and oligoasthenospermic men compared with no rmospermic subjects,which suggest a reduced activity of the PI3K/AKT pathway in these in fertile subjects.Importantly,these sperm from infertile subjects also have a significantly(P<0.05)lower level of phospho-PHB(pT258).Collectively,our findings suggest that the interaction of PHB with AKT in the mitochondrial sheath is critical for sperm motility,where PHB phosphorylation(pT258)level and PI3K/AKT activity are key regulatory factors.展开更多
Cytosine base editing achieves C·G-to-T·A substitutions and can convert four codons(CAA/CAG/CGA/TGG)into STOP-codons(induction of STOP-codons,iSTOP)to knock out genes with reduced mosaicism.iSTOP enables dir...Cytosine base editing achieves C·G-to-T·A substitutions and can convert four codons(CAA/CAG/CGA/TGG)into STOP-codons(induction of STOP-codons,iSTOP)to knock out genes with reduced mosaicism.iSTOP enables direct phenotyping in founders’somatic cells,but it remains unknown whether this works in founders’germ cells so as to rapidly reveal novel genes for fertility.Here,we initially establish that iSTOP in mouse zygotes enables functional characterization of known genes in founders’germ cells:Cfap43-iSTOP male founders manifest expected sperm features resembling human“multiple morphological abnormalities of the flagella”syndrome(i.e.,MMAF-like features),while oocytes of Zp3-iSTOP female founders have no zona pellucida.We further illustrate iSTOP’s utility for dissecting the functions of unknown genes with Ccdc183,observing MMAF-like features and male infertility in Ccdc183-iSTOP founders,phenotypes concordant with those of Ccdc183-KO offspring.We ultimately establish that CCDC183 is essential for sperm morphogenesis through regulating the assembly of outer dynein arms and participating in the intra-flagellar transport.Our study demonstrates iSTOP as an efficient tool for direct reproductive disease modeling and phenotyping in germ cells of the founder generation,and rapidly reveals the essentiality of Ccdc183 in fertility,thus providing a time-saving approach for validating genetic defects(like nonsense mutations)for human infertility.展开更多
Dear Editor,Tetralogy of Fallot(TOF)is the most common complex congenital heart disease.Besides gene mutations and copy number variants,altered protein function induced by posttranscriptional or translational regulati...Dear Editor,Tetralogy of Fallot(TOF)is the most common complex congenital heart disease.Besides gene mutations and copy number variants,altered protein function induced by posttranscriptional or translational regulation also contributes to the onset of TOF.1 MiRNAs are short noncoding RNAs that bind to the 3’-UTR of target mRNAs to repress protein production.However,the causal link between miRNAs and TOF and the underlying mechanism has not been established.展开更多
Objective:Increasing evidences have shown that prepregnancy maternal weight and gestational weight gain(GWG)may associate with offspring’s neurodevelopment.However,the effects of prepregnancy maternal overweight,obes...Objective:Increasing evidences have shown that prepregnancy maternal weight and gestational weight gain(GWG)may associate with offspring’s neurodevelopment.However,the effects of prepregnancy maternal overweight,obesity,and excessive GWG on offspring’s intelligence remain controversial.This meta-analysis aimed to re-assess the association between prepregnancy body mass index(BMI),GWG,and children’s intelligence.Methods:We systematically searched multiple databases,including PubMed,EMBASE,Cochrane Library,and Ovid Medline,from their inception through February 2021.Studies assessing the association between prepregnancy BMI or GWG and children’s intelligence were further screened manually before final inclusion.Cohorts that analyzed the association between prepregnancy BMI or GWG and intelligence of offspring were included,and we used the Mantel-Haenszel fixed-effects method to compute the weighted mean difference(WMD)and 95%confidence interval(CI)of each study.Results:A total of 12 articles were included in this systematic review,while six of them in the meta-analysis.There was a significant full-scale IQ reduction in children born from overweight and obese mothers,with WMDs of-3.08(95%CI:-4.02,-2.14)and-4.91(95%CI:-6.40,-3.42),respectively.Compared with control group,the WMDs for performance and verbal intelligence quotient(IQ)were decreased in overweight and obesity groups.However,we observed no association between children’s full-scale IQ and excessive GWG with WMD of-0.14(95%CI:-0.92,0.65).Conclusions:Women’s prepregnancy overweight and obesity adversely associate with children’s intelligence but no association with excessive GWG.Our study suggests that further researches focusing on the effect of prepregnancy maternal health on offspring’s intelligence development are needed.展开更多
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
基金jointly supported by the National Key Research and Development Program of China(2018YFC1002104 to L.W.,2018YFC1004904 to B.-L.W.and J.F.,2016YFC1000500 to H.Y.W.and W.F.T.)the National Natural Science Foundation of China([81930036,31521003,31771669]to H.Y.W.)+1 种基金the Commission for Science and Technology of Shanghai Municipality(17JC1400902to H.Y.W.)the MDA-CHB Research Grant to B.-L.W。
文摘Polycystic ovary syndrome(PCOS)is a heterogeneous disorder with evidence of polygenetic components,and obesity may be a risk factor for hyperandrogen ism.Previous studies have shown that LHCGR is en riched in the ovary and LHCGR deficiency causes infertility without typical PCOS phenotypes.ALMS1 is implicated in obesity and hyperandrogenism,the common phenotypes among PCOS patients.Through whole-exome sequencing of 22 PCOS families and targeted candidate gene sequencing of additional 65 sporadic PCOS patients,we identified potential causative mutations in LHCGR and ALMS1 in a sibling-pair PCOS family and three sporadic PCOS patients.The expression of LHCGRL638 P in granulosa-like tumor cell line(KGN)cells promoted cyclic adenosine monophosphate production and granulosa cell proliferation,indicating that LHCGRL638 P is an activating mutation.Lhcgr~(L642 P/L642 P)mice showed an irregular estrous cycle,reduced follicles with dynamic folliculogenesis,and increased testosterone(T),estradiol(E2),and dehydroepiandrosterone.Lhcgr~(+/L642 P)AIms1~(+/PB)mice displayed increased T and E2 but decreased late secondary and preovulatory follicles.We showed that activating mutation of LHCGR likely plays important roles in the pathophysiology of PCOS involving abnormal reproductive physiology,whereas ALMS1 deficiency may promote anovulatory infertility via elevated androgens,suggesting that the disturbed LHCGR and ALMS1 cooperatively induce PCOS phenotypes,characterized as anovulation and hyperandrogenemia frequently observed in PCOS patients with obesity.
基金supported by the National Natural Science Foundation of China(82071700,82101679,and 32288101)The University Synergy Innovation Program of Anhui Province in China(GXXT-2021-071).
文摘Globally,infertility is a serious health problem affecting about 15%of reproductive age couples according to the data reported by the World Health Organization.Non-obstructive azoospermia(NOA)is acknowledged as one of the most serious phenotypes of male infertility.Approximately 1%of the male population and 10%of infertile men were affected by NOA(Xie et al.,2022).As reported,meiotic arrest is one of the major etiologies leading to the NOA.
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 Basic Research Program of China(No.2012CB944600)the National Key Research and Development Program of China(No.2016YFC0905100)+1 种基金the National Natural Science Foundation of China(Nos.31521003,31625015,31571297,31601046,31525014 and 91331204)the Science and Technology Commission of Shanghai Municipality(No.16YF1413900)
文摘Human genetic variants have long been known to play an important role in both Mendelian disorders and common diseases. Notably, pathogenic variants are not limited to single-nucleotide variants. It has become apparent that human diseases can also be caused by copy number variations （CNVs）, especially patient- specific novel CNVs （lafrate et al., 2004; Sebat et al., 2004; Redon et al., 2006; LuDski, 2007; Zhan~ et al.. 2009： Wu et al.. 2015）.
基金supported by Research and Development Program of China(2016YFC1000500)to H.W.and W.T.the National Natural Science Foundation of China(81430005,31521003,31771669)to H.W.and(31601029)to Y.G.the Commission for Science and Technology of Shanghai Municipality(17JC1400902)to H.W.
文摘Wnt signaling pathways,including the canonical Wnt/β-catenin pathway,planar cell polarity pathway,and Wnt/Ca2+signaling pathway,play important roles in neural development during embryonic stages.The DVL genes encode the hub proteins for Wnt signaling pathways.The mutations in DVL2 and DVL3 were identified from patients with neural tube defects(NTDs),but their functions in the pathogenesis of human neural diseases remain elusive.Here,we sequenced the coding regions of three DVL genes in 176 stillborn or miscarried fetuses with NTDs or Dandy-Walker malformation(DWM)and 480 adult controls from a Han Chinese population.Four rare mutations were identified:DVL1 p.R558 H,DVL1 p.R606 C,DVL2 p.R633 W,and DVL3 p.R222 Q.To assess the effect of these mutations on NTDs and DWM,various functional analyses such as luciferase reporter assay,stress fiber formation,and in vivo teratogenic assay were performed.The results showed that the DVL2 p.R633 W mutation destabilized DVL2 protein and upregulated activities for all three Wnt signalings(Wnt/β-catenin signaling,Wnt/planar cell polarity signaling,and Wnt/Ca2+signaling)in mammalian cells.In contrast,DVL1 mutants(DVL1 p.R558 H and DVL1 p.R606 C)decreased canonical Wnt/β-catenin signaling but increased the activity of Wnt/Ca2+signaling,and DVL3 p.R222 Q only decreased the activity of Wnt/Ca2+signaling.We also found that only the DVL2 p.R633 W mutant displayed more severe teratogenicity in zebrafish embryos than wild-type DVL2.Our study demonstrates that these four rare DVL mutations,especially DVL2 p.R633 W,may contribute to human neural diseases such as NTDs and DWM by obstructing Wnt signaling pathways.
基金supported by the National Key Research and Development Program of China(2021YFC2701400)in part by the National Natural Science Foundation of China(32000393 and 32288101).
文摘During spermiogenesis,haploid spermatids undergo dramatic morphological changes to form slender sperm flagella and cap-like acrosomes,which are required for successful fertilization.Severe deformities in flagella cause a male infertility syndrome,multiple morphological abnormalities of the flagella(MMAF),while acrosomal hypoplasia in some cases leads to sub-optimal embryonic developmental potential.However,evidence regarding the occurrence of acrosomal hypoplasia in MMAF is limited.Here,we report the generation of base-edited mice knocked out for coiled-coil domain-containing 38(Ccdc38)via inducing a nonsense mutation and find that the males are infertile.The Ccdc38-KO sperm display acrosomal hypoplasia and typical MMAF phenotypes.We find that the acrosomal membrane is loosely anchored to the nucleus and fibrous sheaths are disorganized in Ccdc38-KO sperm.Further analyses reveal that Ccdc38 knockout causes a decreased level of TEKT3,a protein associated with acrosome biogenesis,in testes and an aberrant distribution of TEKT3 in sperm.We finally show that intracytoplasmic sperm injection overcomes Ccdc38-related infertility.Our study thus reveals a previously unknown role for CCDC38 in acrosome biogenesis and provides additional evidence for the occurrence of acrosomal hypoplasia in MMAF.
基金This work was supported by Shanghai Municipal Science and Technology Major Project(No.2017SHZDZX01).
文摘Dear Editor,The most severe type of male infertility,nonobstructive azoospermia(NOA),is characterized by clinical heterogeneity,implying the involvement of different acquired and genetic factors.However,the cause of NOA is unidentified in a substantial number of patients after the exclusion of all-known acquired factors and routine genetic testing,such as karyotype and Y chromosome microdeletion analysis.1 With the recent rapid development of whole-exome sequencing(WES),an increasing number of novel monogenic causes have been identified.Recently,RAD51-associated protein 2(RAD51AP2)was reported to be a novel causative gene of NOA in a monogenic recessive manner in two sporadic patients.2 Here,we studied the WES data for a family with two NOA patients and found that both carried a novel homozygous loss-of-function(LoF)mutation in RAD51AP2.
文摘Genetic factors play important roles in the etiology of male infertility.The routine clinical genetic testing for human spermatogenic failure is currently limited to abnormal karyotypes(e.g,47,XXY for Klinefelter syndrome)and Y chromosomal microdeletions.^(1)However,these chromosomal variants only account for approximately 20%of the infertile males with nonobstructive azoospermia.The vast majority of male infertile cases are genetically unexplained.With the recent advances in genomic technologies,the genome-wide dissections at the nucleotide resolution have been achieved,and the novel genetic factors involved in human male infertility have been continuously uncovered.Furthermore.
基金supported by the National Key R&D Program of China(2021YFC2701101 to H.W.and X.Y.)the National Natural Science Foundation of China(81930036 and 82150008 to H.W.,and 31000542 to X.Y.)the Commission of Science and Technology of Shanghai Municipality(20JC1418500 to H.W.).
文摘T-box transcription factor T(TBXT;T)is required for mesodermal formation and axial skeletal development.Although it has been extensively studied in various model organisms,human congenital vertebral malformations(CVMs)involving T are not well established.Here,we report a family with 15 CVM patients distributed across 4 generations.All affected individuals carry a heterozygous mutation,T c.596A>G(p.Q199R),which is not found in unaffected family members,indicating co-segregation of the genotype and phenotype.In vitro assays show that T p.Q199R increases the nucleocytoplasmic ratio and enhances its DNA-binding affinity,but reduces its transcriptional activity compared to the wild-type.To determine the pathogenicity of this mutation in vivo,we generated a Q199R knock-in mouse model that recapitulates the human CVM phenotype.Most heterozygous Q199R mice show subtle kinked or shortened tails,while homozygous mice exhibit tail filaments and severe vertebral deformities.Overall,we show that the Q199R mutation in T causes CVM in humans and mice,providing previously unreported evidence supporting the function of T in the genetic etiology of human CVM.
基金supported by the National Natural Science Foundation of China(32270658 and 32288101)the National Key Research and Development Program of China(2022YFC2703800)the Natural Science Foundation of Shanghai(20ZR1407000).
文摘Premature ovarian insufficiency(POI)is a severe female reproductive disorder that affects 1%of women in general populations(European Society for Human Reproduction and Embryology[ESHRE]Guideline Group on POI et al.,2016).An increasing prevalence up to 3.7%has been reported in a recent meta-analysis(Golezar et al.,2019).POl can lead to infertility or subfertility,as well as a range of complex complications suffering multi-organ systems,seriously threatening women's health and reducing the life quality.By contrast,POl is a representative heterogeneous disease with multiple etiologies.While more than 70 causative POI genes have been identified,the etiology of more than half of the POI patients is still ambiguous(Jiao et al.,2018).Unreported POI causative genes,therefore,remain to be identified.
文摘Huang et al.[1]have put forward reasonable suggestions regarding certain findings of our recently published article,specifically including:(i)the cut-off values and limitations of the Edinburgh Postnatal Depression Scale(EPDS);(ii)the restriction of data collection in our study to the third trimester;(iii)the sampling methodology employed in this study;(iv)the use of binary versus ternary classification for EPDS scores;(v)the lack of 95%confidence intervals for prevalence estimates;and(vi)the assessment of participants’prior mental health history.As described in this Reply,we interpreted the results of our article by reviewing and referring to other published articles.
基金supported by National Key Research and Development Program of China(2022YFC2703500)National Natural Science Foundation of China(8211101588,82088102 and 82171686)+10 种基金Program of Shanghai Academic Research Leader(20XD1424100)Natural Science Foundation of Shanghai(20ZR1463100)Clinical research program of Shanghai Municipal Health Commission(202340222)Collaborative Innovation Program of Shanghai Municipal Health Commission(2020CXJQ01)Clinical Research Plan of Shanghai Shenkang Hospital Development Center(SHDC2023CRD001 and SHDC2020CR1008A)STI2030-Major Projects(2021ZD0200700)CAMS Innovation Fund for Medical Sciences(2019-I2M-5–064)Shanghai Clinical Research Center for Gynecological Diseases(22MC1940200)Shanghai Urogenital System Diseases Research Center(2022ZZ01012)Key Discipline Construction Project(2023–2025)of Three-Year Initiative Plan for Strengthening Public Health System Construction in Shanghai(GWVI-11.1–35)the specific research fund of the Innovation Platform for Academicians of Hainan Province(YSPTZX202311)and Shanghai Frontiers Science Research Base of Reproduction and Development.
文摘Background While maternal psychological stress during mid-to-late pregnancy has been linked to offspring allergies,the impact of early pregnancy distress remains unclear.This study investigates the association between maternal depressive and anxiety symptoms in early pregnancy and allergic diseases in offspring.Methods Based on a birth cohort of 5263 children,antenatal depressive and anxiety symptoms in early pregnancy were assessed via the Patient Health Questionnaire and Generalized Anxiety Disorder Questionnaire,respectively.Allergic outcomes,including asthma,atopic dermatitis(AD),and allergic rhinitis(AR),were evaluated via structured questionnaires.Relative risks(RRs)with 95%confidence intervals(CIs)were estimated via generalized linear models,whereas restricted cubic splines were used to explore linear and non-linear associations between maternal distress and allergic outcomes.Results Maternal depressive symptoms in early pregnancy were associated with an increased risk of AD[adjusted RR(95%CI)=1.15(1.03–1.29)]and AR[1.52(1.29–1.79)].Maternal anxiety symptoms in early pregnancy were associated with increased risks of AD[1.11(1.02–1.21),mild anxiety]and AR[1.33(1.04–1.68),moderate to severe anxiety].Dose‒response analyses revealed graded relationships between distress severity and allergic outcomes.In the joint analysis,comorbid depression and anxiety in early pregnancy were associated with an increased risk of AD[1.15(1.05–1.26)]and AR[1.42(1.23–1.63)].Subgroup analysis revealed a greater risk of asthma for boys born to mothers with mild anxiety[1.95(1.20–3.15)]but not for girls.Conclusion Maternal distress in early pregnancy is associated with an increased risk of allergic diseases in offspring during toddlerhood.
基金supported by the STI2030-Major Projects(2021ZD0200700)the National Key Research and Development Program of China(2021YFC2701600 and 2022YFC2703500)+10 种基金the National Natural Science Foundation of China(82088102 and 82301719)Science and Technology Innovation Fund of Shanghai Jiao Tong University(YG2020YQ29)Collaborative Innovation Program of Shanghai Municipal Health Commission(2020CXJQ01)Shanghai Municipal Commission of Health(20224Y0085 and 202340222)Open Fund Project of Guangdong Academy of Medical Sciences(YKY-KF202202)CAMS Innovation Fund for Medical Sciences(2019-I2M-5-064)Shanghai Clinical Research Center for Gynecological Diseases(22MC1940200)Shanghai Urogenital Sys-tem Diseases Research Center(2022ZZ01012)Key Discipline Con-struction Project(2023-2025)of Three-Year Initiative Plan for Strengthening Public Health System Construction in Shanghai(GWVI-11.1-35 and GWVI-11.2-YQ29)Shanghai Sailing Program(22YF1453100)Shanghai Frontiers Science Research Base of Reproduction and Development.
文摘Antenatal depression is a significant contributor to maternal morbidity in the perinatal period[1].It has also been associated with an increased risk for premature delivery,decreased rates of breastfeeding initiation,and a broad range of adverse child out-comes,including emotional problems,externalizing difficulties,attachment issues,and poorer cognitive development[2-6]Depression in the antenatal period may persist postnatally and increase in severity further exacerbating the negative conse-quences.There are considerable geographical differences in ante-natal depression prevalence rates across China,ranging from 9.8%to 35.4%,which is likely due to variations in demographic,lifestyle,social,and economic factors[7,8].Heterogeneity in study design and data source has also resulted in these wide variations.Further,previous Chinese studies examining antenatal depression have been limited due to relatively small sample sizes,short study peri-ods,and a focus on only one specific geographical district.Limited prevalence data in China suggest that a large-scale multi-center study is warranted.
基金This project was funded by grants from the National Natural Science Foundation of China(No.81270738)and the Major State Basic Research Development Program of China(No.2014CB943104).
文摘Prohibitin(PHB),an evoluti on arily con served mitochondrial inner membra ne protein,is highly expressed in cells that require strong mitoch on drial function.Recently,we dem on strated that the deleti on of Phb in spermatocytes results in impaired mitochondrial function.In addition,PHB expression in the mitochondrial sheath of human sperm has a significantly negative correlation with mitochondrial reactive oxygen species levels,but a positive one with mitochondrial membrane potential and sperm motility.These results suggest that mitochondrial PHB expression plays a role in sperm motility.However,the mechanism of PHB-mediated regulation of sperm motility remai ns unk nown.Here,we dem on strate for the first time that PHB interacts with protei n kinase B(AKT)and exists in a complex with phospho-PHB(pT258)and phospho-AKT in the mitochondrial sheath of murine sperm,as determined using colocalization and coimmunoprecipitation assays.After blocking AKT activity using wortmannin(a phosphatidylinositol 3-kinase[PI3K]inhibitor),murine sperm have significantly(P<0.05)decreased levels of phospho-PHB(pT258)and the total and progressive motility.Furthermore,significantly(P<0.05)lower levels of phospho-PI3K P85 subunit a+γ(pY199 and pY46)and phospho-AKT(pS473;pT308)are found in sperm from infertile asthenospermic and oligoasthenospermic men compared with no rmospermic subjects,which suggest a reduced activity of the PI3K/AKT pathway in these in fertile subjects.Importantly,these sperm from infertile subjects also have a significantly(P<0.05)lower level of phospho-PHB(pT258).Collectively,our findings suggest that the interaction of PHB with AKT in the mitochondrial sheath is critical for sperm motility,where PHB phosphorylation(pT258)level and PI3K/AKT activity are key regulatory factors.
基金supported by the National Key Research and Development Program of China(2021YFC2701400)the National Natural Science Foundation of China(32000393,32322017,32288101)。
文摘Cytosine base editing achieves C·G-to-T·A substitutions and can convert four codons(CAA/CAG/CGA/TGG)into STOP-codons(induction of STOP-codons,iSTOP)to knock out genes with reduced mosaicism.iSTOP enables direct phenotyping in founders’somatic cells,but it remains unknown whether this works in founders’germ cells so as to rapidly reveal novel genes for fertility.Here,we initially establish that iSTOP in mouse zygotes enables functional characterization of known genes in founders’germ cells:Cfap43-iSTOP male founders manifest expected sperm features resembling human“multiple morphological abnormalities of the flagella”syndrome(i.e.,MMAF-like features),while oocytes of Zp3-iSTOP female founders have no zona pellucida.We further illustrate iSTOP’s utility for dissecting the functions of unknown genes with Ccdc183,observing MMAF-like features and male infertility in Ccdc183-iSTOP founders,phenotypes concordant with those of Ccdc183-KO offspring.We ultimately establish that CCDC183 is essential for sperm morphogenesis through regulating the assembly of outer dynein arms and participating in the intra-flagellar transport.Our study demonstrates iSTOP as an efficient tool for direct reproductive disease modeling and phenotyping in germ cells of the founder generation,and rapidly reveals the essentiality of Ccdc183 in fertility,thus providing a time-saving approach for validating genetic defects(like nonsense mutations)for human infertility.
基金supported by grants from the National Key R&D Program of China(2021YFC2701101,H.W.)the National Natural Science Foundation of China(81930036 and 82150008,H.W.)the Commission for Science and Technology of Shanghai Municipality(20JC1418500,H.W.).
文摘Dear Editor,Tetralogy of Fallot(TOF)is the most common complex congenital heart disease.Besides gene mutations and copy number variants,altered protein function induced by posttranscriptional or translational regulation also contributes to the onset of TOF.1 MiRNAs are short noncoding RNAs that bind to the 3’-UTR of target mRNAs to repress protein production.However,the causal link between miRNAs and TOF and the underlying mechanism has not been established.
基金Program of Shanghai Academic Research Leader(20XD1424100)Shanghai Hospital Development Center(SHDC12018X17)+1 种基金Shanghai Municipal Health Commission(201840210)Science and Technology Commission of Shanghai Municipality(18410711800)。
文摘Objective:Increasing evidences have shown that prepregnancy maternal weight and gestational weight gain(GWG)may associate with offspring’s neurodevelopment.However,the effects of prepregnancy maternal overweight,obesity,and excessive GWG on offspring’s intelligence remain controversial.This meta-analysis aimed to re-assess the association between prepregnancy body mass index(BMI),GWG,and children’s intelligence.Methods:We systematically searched multiple databases,including PubMed,EMBASE,Cochrane Library,and Ovid Medline,from their inception through February 2021.Studies assessing the association between prepregnancy BMI or GWG and children’s intelligence were further screened manually before final inclusion.Cohorts that analyzed the association between prepregnancy BMI or GWG and intelligence of offspring were included,and we used the Mantel-Haenszel fixed-effects method to compute the weighted mean difference(WMD)and 95%confidence interval(CI)of each study.Results:A total of 12 articles were included in this systematic review,while six of them in the meta-analysis.There was a significant full-scale IQ reduction in children born from overweight and obese mothers,with WMDs of-3.08(95%CI:-4.02,-2.14)and-4.91(95%CI:-6.40,-3.42),respectively.Compared with control group,the WMDs for performance and verbal intelligence quotient(IQ)were decreased in overweight and obesity groups.However,we observed no association between children’s full-scale IQ and excessive GWG with WMD of-0.14(95%CI:-0.92,0.65).Conclusions:Women’s prepregnancy overweight and obesity adversely associate with children’s intelligence but no association with excessive GWG.Our study suggests that further researches focusing on the effect of prepregnancy maternal health on offspring’s intelligence development are needed.
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).
