Abstract:
STUDY QUESTION:Does a heterozygous mutation in AMHR2, identified in whole-exome sequencings (WES) of patients with primary ovarian insufficiency (POI), cause a defect in anti-Müllerian hormone (AMH) signaling? SUMMARY ANSWER:The I209N mutation at the adenosine triphosphate binding domain of AMHR2 exerts dominant negative defects in the AMH signaling pathway. WHAT IS KNOWN ALREADY:Previous studies have demonstrated the associations of several sequence variants in AMH or AMHR2 with POI, but no functional assay has been performed to verify whether there was any defect on AMH signaling. STUDY DESIGN, SAMPLES/MATERIALS, METHODS:Ninety-six unrelated female Chinese Han patients were diagnosed with idiopathic POI and subjected to WES. In silico analysis was done for the sequence variants followed by molecular assays to examine the functional effects of the sequence variants in human granulosa cells. In silico analysis, immunostaining, Western analysis, genome-wide expression analysis, quantitatively polymerase chain reaction were applied to the characterization of the sequence variants. MAIN RESULTS AND THE ROLE OF CHANCE:We identified one novel heterozygous missense variant, p.Ala17Glu (A17E), in AMHR2. Subsequently, A17E and two independently reported missense variants, p.Ile209Asn (I209N) and p.Leu354Phe (L354F), were evaluated for effects on the AMH signaling pathway. In silico analysis predicted that all three variants may be deleterious. However, only one variant, I209N, showed severe defects in transducing the AMH signal as well as impaired SMAD1/5/8 phosphorylation. Furthermore, using genome-wide gene expression analysis, we identified genes whose expression was affected by the mutation, these included genes previously reported to participate in AMH signaling as well as newly identified genes. They are EMILIN2, FAM155A, GATA2, HES5, ID1, ID2, RLTPR, SMAD7, CBL, MALAT1 and SMARCA2. LARGE SCALE DATA:None. LIMITATIONS, REASONS FOR CAUTION:Although the in vitro assays demonstrated the causative effect of I209N on AMH signaling, further studies need to validate its long-term effects on folliculogenesis and POI. WIDER IMPLICATIONS OF THE FINDINGS:These results will aid both researchers and clinicians in understanding the molecular pathology of AMH signaling and POI to develop diagnostic assays or therapeutics approaches. STUDY FUNDING AND COMPETING INTERESTS:Research funding is provided by the Ministry of Science and Technology of China [2012CB944704; 2012CB966702], and the National Natural Science Foundation of China [Grant number: 31171429]. The authors declare no conflict of interest.
journal_name
Mol Hum Reprodjournal_title
Molecular human reproductionauthors
Li L,Zhou X,Wang X,Wang J,Zhang W,Wang B,Cao Y,Kee Kdoi
10.1093/molehr/gaw040subject
Has Abstractpub_date
2016-09-01 00:00:00pages
669-78issue
9eissn
1360-9947issn
1460-2407pii
gaw040journal_volume
22pub_type
杂志文章abstract::The androgen receptor (AR) gene is located on the X chromosome and contains a polymorphic CAG tract. CAG repeat expansions in the AR have been associated with male infertility and the neuromuscular disease, spinal bulbar muscular atrophy (SBMA). Based on Mendelian inheritance patterns, moderate CAG expansions in infer...
journal_title:Molecular human reproduction
pub_type: 杂志文章
doi:10.1093/molehr/6.9.861
更新日期:2000-09-01 00:00:00
abstract::Villous tissues from 30 spontaneous abortions and the same number of artificial abortions were obtained and analysed for the frequency of polyploid cells. Single cell suspensions were made from these tissues without culture and the ploidy of > 100 cells was analysed. Trisomies of chromosomes 17 and 4 have rarely been ...
journal_title:Molecular human reproduction
pub_type: 杂志文章
doi:10.1093/molehr/3.5.445
更新日期:1997-05-01 00:00:00
abstract::Spermatogenesis is a highly programmed process that requires the degradation of the extracellular matrix and the remodeling of tight junctions (TJ) to facilitate differentiating germ cell migration. Matrix metalloproteinases (MMPs) are essential in regulating Sertoli cell TJ in the testis. CD147 is known to stimulate ...
journal_title:Molecular human reproduction
pub_type: 杂志文章
doi:10.1093/molehr/gar013
更新日期:2011-07-01 00:00:00
abstract::Genes containing the evolutionarily conserved homeodomain sequence encode a family of DNA-binding transcription factors whose functions are crucial for embryonic development in vertebrates, invertebrates and plants. We describe the detection and analysis of transcripts of homeobox-containing genes present in cDNA libr...
journal_title:Molecular human reproduction
pub_type: 杂志文章
doi:10.1093/molehr/6.8.707
更新日期:2000-08-01 00:00:00
abstract::The maternal aorta undergoes substantial functional and structural adaptation in pregnancy. Both aortic diameter and compliance are increased and studies of animal and human gestation indicate that these changes are initiated in early pregnancy and maintained until delivery. The mechanisms underlying aortic adaptation...
journal_title:Molecular human reproduction
pub_type: 杂志文章
doi:10.1093/humrep/gah045
更新日期:2004-05-01 00:00:00
abstract::Etoposide is widely used in the treatment of patients with testicular cancer. The mechanism underlying apoptosis induction in cancer cells has been studied in different cell types, but it is not known whether the same factors participate in viable germ cells undergoing programmed cell death. Since testicular cancer pr...
journal_title:Molecular human reproduction
pub_type: 杂志文章
doi:10.1093/molehr/gap024
更新日期:2009-06-01 00:00:00
abstract::Embryo implantation and subsequent decidualization, trophoblast invasion and formation of a functional placenta are crucial for establishment and maintenance of pregnancy. Interleukin-11 signalling has been shown to be obligatory for adequate decidualization and trophoblast invasion in mice. Defects in IL-11 signallin...
journal_title:Molecular human reproduction
pub_type: 杂志文章
doi:10.1093/molehr/gah107
更新日期:2004-11-01 00:00:00
abstract::Mammalian sperm undergo a series of maturation steps before acquiring fertilization competence. Our previous work demonstrated the importance of binder of sperm (BSP) proteins in bovine sperm capacitation. Recent studies identified a BSP-homologous DNA sequence in the human genome (BSPH1) and mRNA expression in the ep...
journal_title:Molecular human reproduction
pub_type: 杂志文章
doi:10.1093/molehr/gan077
更新日期:2009-02-01 00:00:00
abstract::Oxidative damage by reactive oxygen species (ROS) is a major cause of sperm dysfunction. Excessive ROS generation reduces fertilization and enhances DNA damage of spermatozoa. Interaction between spermatozoa and oviductal epithelial cells improves the fertilizing ability of and reduces chromatin damage in spermatozoa....
journal_title:Molecular human reproduction
pub_type: 杂志文章
doi:10.1093/molehr/gav015
更新日期:2015-06-01 00:00:00
abstract::Zinc dynamics are essential for oocyte meiotic maturation, egg activation, and preimplantation embryo development. During fertilisation and egg activation, the egg releases billions of zinc atoms (Zn2+) in an exocytotic event termed the 'zinc spark'. We hypothesised that this zinc transport and exocytosis is dependent...
journal_title:Molecular human reproduction
pub_type: 杂志文章
doi:10.1093/molehr/gaaa017
更新日期:2020-04-24 00:00:00
abstract::FSH is a pituitary gonadotropin that along with LH plays a key role in the regulation of gonadal function. The gonadotropic hormones are composed of two subunits, the common alpha subunit and the hormone-specific beta subunit, which determines the binding to specific receptors and induction of biological response. Unl...
journal_title:Molecular human reproduction
pub_type: 杂志文章
doi:10.1093/molehr/gah198
更新日期:2005-08-01 00:00:00
abstract::Oxidative stress is a major aetiology in many pathologies, including that of male infertility. Recent evidence in somatic cells has linked oxidative stress to the induction of a novel cell death modality termed ferroptosis. However, the induction of this iron-regulated, caspase-independent cell death pathway has never...
journal_title:Molecular human reproduction
pub_type: 杂志文章
doi:10.1093/molehr/gaz015
更新日期:2019-05-01 00:00:00
abstract::Cytogenetically, uterine leiomyomata are the best investigated human tumours. The most frequent clonal abnormalities are structural rearrangements involving 12q14-15 and deletions of part of the long arm of chromosome 7. The present study investigated a possible growth advantage conferred by these abnormalities, when ...
journal_title:Molecular human reproduction
pub_type: 杂志文章
doi:10.1093/molehr/5.12.1150
更新日期:1999-12-01 00:00:00
abstract:STUDY QUESTION:Is it possible to identify original compounds that are able to enhance sperm motility from the venom of the scorpion Scorpio maurus palmatus? SUMMARY ANSWER:We identified a potent disulfide-rich peptide (DRP) of 73 amino acids that significantly improved the motility of fresh and frozen-thawed sperm in ...
journal_title:Molecular human reproduction
pub_type: 杂志文章
doi:10.1093/molehr/gaw075
更新日期:2017-02-10 00:00:00
abstract::It is well known that human embryonic stem cells (hESCs) frequently acquire recurrent chromosomal abnormalities, very reminiscent of those found in cancerous cells. Given the parallels between cancer and stem cell biology, we set out to investigate the occurrence of a common form of genome instability in tumors, namel...
journal_title:Molecular human reproduction
pub_type: 杂志文章
doi:10.1093/molehr/gau059
更新日期:2014-10-01 00:00:00
abstract::Oligozoospermia (low sperm count) is a common semen deficiency. However, to date, few genetic defects have been identified to cause this condition. Moreover, even fewer molecular genetic diagnostic tests are available for patients with oligozoospermia in the andrology clinic. Based on animal and gene expression studie...
journal_title:Molecular human reproduction
pub_type: 杂志文章
doi:10.1093/molehr/gat008
更新日期:2013-06-01 00:00:00
abstract::Cytokines are important regulators of reproductive functions. Significant amounts of interleukin-6 (IL-6) have been detected in the serum and ascites of patients with ovarian hyperstimulation syndrome (OHSS). These findings suggest the involvement of IL-6 as a mediator in the pathogenesis of OHSS. This study was perfo...
journal_title:Molecular human reproduction
pub_type: 杂志文章
doi:10.1093/molehr/4.11.1071
更新日期:1998-11-01 00:00:00
abstract::Inhibin production has been demonstrated in malignant epithelial ovarian tumours, but secretion of inhibins by benign cystadenoma has not yet been reported. The present study evaluated the concentrations of inhibin A and inhibin B and the relationship with oestradiol and nitric oxide metabolites in fluid collected fro...
journal_title:Molecular human reproduction
pub_type: 杂志文章
doi:10.1093/molehr/6.12.1079
更新日期:2000-12-01 00:00:00
abstract::The present study was undertaken to investigate the effect of decidualization on superoxide dismutase (SOD) expression in human endometrial stromal cells (ESC). To induce decidualization, isolated ESC were incubated with medroxyprogesterone acetate (MPA, 10(-6) mol/l) and oestradiol (10(-8) mol/l) for 23 days. Insulin...
journal_title:Molecular human reproduction
pub_type: 杂志文章
doi:10.1093/molehr/6.2.178
更新日期:2000-02-01 00:00:00
abstract::Endometriosis, the presence of ectopic endometrial tissue outside the uterine cavity, is a common disease affecting women during their reproductive years. The aim of this study was to identify the molecular mechanism of transcriptional regulation of inflammatory cyclooxygenase-2 (COX-2) gene during endometriosis by hy...
journal_title:Molecular human reproduction
pub_type: 杂志文章
doi:10.1093/molehr/gar036
更新日期:2011-11-01 00:00:00
abstract::The peri-implantation period is a critical time during murine development. Although the importance of nitric oxide has been demonstrated during gestation, its role in implantation has not been fully defined. The aim of this study was to quantify (by Western blotting) two prominent nitric oxide synthase (NOS) isoforms,...
journal_title:Molecular human reproduction
pub_type: 杂志文章
doi:10.1093/molehr/5.5.467
更新日期:1999-05-01 00:00:00
abstract::We compared latent TGF-ss binding protein-1 (LTBP-1) and fibrillin-1 (FBN-1) expression in leiomyomata and myometrium, correlated with leiomyomata size. We studied in vivo and in vitro effects of ovarian steroids using matched leiomyomata and myometrium samples from both phases of the menstrual cycle. Leiomyomata were...
journal_title:Molecular human reproduction
pub_type: 杂志文章
doi:10.1093/molehr/gam007
更新日期:2007-05-01 00:00:00
abstract::In women with premature ovarian failure, fertility may be preserved by ovarian tissue culture in vitro. However, techniques for tissue culture and follicle maturation have remained suboptimal. Our aim was to characterize ovarian tissue degeneration in cultures and to establish a model for cell death research in cultur...
journal_title:Molecular human reproduction
pub_type: 杂志文章
doi:10.1093/molehr/8.3.228
更新日期:2002-03-01 00:00:00
abstract::A complete hydatidiform mole (CHM) is an abnormal pregnancy with hyperproliferative vesicular trophoblast and no fetal development. Most CHM are sporadic and androgenetic, but recurrent HM have biparental inheritance (BiHM) with disrupted DNA methylation at differentially methylated regions (DMRs) of imprinted loci. S...
journal_title:Molecular human reproduction
pub_type: 杂志文章
doi:10.1093/molehr/gam079
更新日期:2008-01-01 00:00:00
abstract::Polar body emission is a specialized cell division throughout the animal kingdom, serving to reduce chromosome ploidy while preserving the egg cytoplasm. Critical to polar body emission are the asymmetric positioning of the meiotic spindle prior to anaphase, with one pole attached to the oocyte cortex, and the simulta...
journal_title:Molecular human reproduction
pub_type: 杂志文章
doi:10.1093/molehr/gar026
更新日期:2011-05-01 00:00:00
abstract::Chemokines are implicated in the implantation process. The aim of this study was to investigate mRNA expression and protein levels of chemokine receptors CXCR1, CXCR4, CCR5 and CCR2B in human endometrium throughout the menstrual cycle, during HRT and in the human blastocyst. The regulation of chemokine receptors in th...
journal_title:Molecular human reproduction
pub_type: 杂志文章
doi:10.1093/molehr/gag024
更新日期:2003-04-01 00:00:00
abstract::The non-classical major histocompatibility complex molecule, human leukocyte antigen (HLA)-G, is thought to contribute to maternal immune tolerance and successful placentation during pregnancy. Genetic polymorphisms in HLA-G are known to influence expression levels as well as the relative expression of individual prot...
journal_title:Molecular human reproduction
pub_type: 杂志文章
doi:10.1093/molehr/gas041
更新日期:2013-03-01 00:00:00
abstract::Ovaries surgically removed for fertility preservation from a total of 24 women served as a source of human small antral follicles, including the follicular fluid (FF) and the corresponding granulosa cells (GC). The FF was used to evaluate the intrafollicular concentrations of anti-Müllerian hormone (AMH), inhibin-B, e...
journal_title:Molecular human reproduction
pub_type: 杂志文章
doi:10.1093/molehr/gaq001
更新日期:2010-09-01 00:00:00
abstract::Virtually all testicular germ cell tumours originate from a common precursor, the carcinoma in situ (CIS) cell. The precise nature of the molecular mechanisms leading to CIS remains largely unknown. We performed the first systematic analysis of gene expression in testis with CIS compared to normal testis by the differ...
journal_title:Molecular human reproduction
pub_type: 杂志文章
doi:10.1093/molehr/gah059
更新日期:2004-06-01 00:00:00
abstract::Controlling the sex of offspring by the separation of X and Y chromosome-bearing spermatozoa using flow cytometry has been reported as a clinical technique aiding prevention of X-linked diseases. Although this technique has resulted in several hundred normal births in animals and at least one human birth, there is sti...
journal_title:Molecular human reproduction
pub_type: 杂志文章
doi:10.1093/molehr/3.9.821
更新日期:1997-09-01 00:00:00