BBA - Molecular Basis of Disease (v.1822, #12)

Molecular control of rodent spermatogenesis by Sabrina Z. Jan; Geert Hamer; Sjoerd Repping; Dirk G. de Rooij; Ans M.M. van Pelt; Tinke L. Vormer (1838-1850).
Spermatogenesis is a complex developmental process that ultimately generates mature spermatozoa. This process involves a phase of proliferative expansion, meiosis, and cytodifferentiation. Mouse models have been widely used to study spermatogenesis and have revealed many genes and molecular mechanisms that are crucial in this process. Although meiosis is generally considered as the most crucial phase of spermatogenesis, mouse models have shown that pre-meiotic and post-meiotic phases are equally important. Using knowledge generated from mouse models and in vitro studies, the current review provides an overview of the molecular control of rodent spermatogenesis. Finally, we briefly relate this knowledge to fertility problems in humans and discuss implications for future research. This article is part of a Special Issue entitled: Molecular Genetics of Human Reproductive Failure.► Molecular control of spermatogenesis. ► Fertility problems in humans. ► Spermatogenesis is a process in which spermatogonial stem cells give rise to spermatids.
Keywords: Spermatogenesis; Germ cell development; Molecular control; Infertility; Mouse models;

It can be argued that the Y chromosome brings some of the spirit of rock&roll to our genome. Equal parts degenerate and sex-driven, the Y has boldly rebelled against sexual recombination, one of the sacred pillars of evolution. In evolutionary terms this chromosome also seems to have adopted another of rock&roll's mottos: living fast. Yet, it appears to have refused to die young. In this manuscript the Y chromosome will be analyzed from the intersection between structural, evolutionary and functional biology. Such integrative approach will present the Y as a highly specialized product of a series of remarkable evolutionary processes. These led to the establishment of a sex-specific genomic niche that is maintained by a complex balance between selective pressure and the genetic diversity introduced by intrachromosomal recombination. Central to this equilibrium is the “polish or perish” dilemma faced by the male-specific Y genes: either they are polished by the acquisition of male-related functions or they perish via the accumulation of inactivating mutations. Thus, understanding to what extent the idiosyncrasies of Y recombination may impact this chromosome's role in sex determination and male germline functions should be regarded as essential for added clinical insight into several male infertility phenotypes. This article is part of a Special Issue entitled: Molecular Genetics of Human Reproductive Failure.► The clinical relevance of the Y for male reproductive function was analyzed. ► Structural, evolutionary and functional biology were the bases of the analysis. ► The Y is a highly specialized product of a unique chromosome differentiation program. ► Selective pressure and intrachromosomal recombination maintain the Y. ► The occurrence of Y variants associated with reproductive defects is the trade-off.
Keywords: Y chromosome; Sex chromosomes; Spermatogenesis; Infertility; Germline; Evolution;

X chromosomal mutations and spermatogenic failure by Katrien Stouffs; Willy Lissens (1864-1872).
The X and Y chromosomes, the sex chromosomes, are important key players in germ cell development. Both chromosomes contain genes that are uniquely expressed in male spermatogenesis. Furthermore, these chromosomes are special because men only have a single copy of them. These features make the sex chromosomes interesting for studying in view of spermatogenesis defects. The role of the Y chromosome, together with the presence of Yq microdeletions, in male infertility is well established. Less well-understood are the X-linked genes, their expression patterns and potential impact on male infertility. This review provides an overview of the current knowledge on potential spermatogenesis genes that are located on the mouse and human X chromosomes. A summary is given on knock-out mice models in which X-linked genes have been shown to alter spermatogenesis, and on genes that have been studied in humans. Finally, new research areas like miRNA analysis, Genome Wide Association Studies (GWAS) and array comparative genomic hybridisation (CGH) studies are discussed. This article is part of a Special Issue entitled: Molecular Genetics of Human Reproductive Failure.►Knock-out mice models for X chromosomal genes. ►Mutation studies in X chromosomal genes in men. ►X chromosomal miRNAs. ►Large scale X chromosomal studies.
Keywords: X chromosome; Spermatogenesis; Infertility;

Autosomal mutations and human spermatogenic failure by Elias El Inati; Jean Muller; Stéphane Viville (1873-1879).
Infertility, defined as the inability to conceive after 1 year of unprotected intercourse, is a healthcare problem that has a worldwide impact. Male factors are involved in at least half of these cases of infertility. Despite 33 years of assisted reproductive activities, a considerable number of cases (25–30%) remain idiopathic. This situation can be explained by a poor understanding of the basic mechanisms driving male and female gametogenesis. Compared to multi-organ pathologies, only a few non-syndromic genetic causes of human infertility have been described so far, despite the fact that it is estimated that some infertility cases could be explained by genetic causes and that over 200 infertile or subfertile genetic mouse models have been described. So far, very little has been discovered in the field of human male reproductive genetics. Consequently, genetic tests proposed to infertile couples are limited, although worldwide efforts devoted to the field of human genetics of infertility are expected to provide new genetic tests in the near future. We present the requirements for performing informative genetics studies in the field of infertility, the techniques used and the results obtained so far. This article is part of a Special Issue entitled: Molecular Genetics of Human Reproductive Failure.► Infertility is a healthcare problem that has a worldwide impact. ► Male factors are involved in at least half of these cases of infertility. ► A considerable number of cases (25 to 30%) remain idiopathic. ► Only few non-syndromic genetic causes of human infertility have been described. ► Consequently, genetic tests proposed to infertile couples are limited.
Keywords: Male infertility; Spermatogenesis; Genetic causes; Gene; Non-syndromic;

Genetics and molecular biology have been instrumental for a better understanding of heritable defects causing human infertility over the past decades. More recently, the field of reproductive biology has harnessed genome biological approaches to gain insight into molecular processes underlying normal and pathological gametogenesis and gamete function. We are currently witnessing yet another quantum leap in our ability to monitor the flow of information from the genome via the transcriptome to the proteome: tiling arrays that cover both strands of a given target genome and RNA-Seq, a method based on ultra-high throughput DNA sequencing, enable us to study noncoding and protein-coding transcripts with unprecedented precision and depth at a reasonable cost. These technologies have spawned a thriving discipline within the bioinformatics field that employs information technology for managing and interpreting biological high-throughput data. This review outlines database projects and online analysis tools useful for life scientists in general and discusses in detail selected projects that have specifically been developed for researchers and clinicians in the field of reproductive biology. This article is part of a Special Issue entitled: Molecular Genetics of Human Reproductive Failure.► GermOnline cross-species array database. ► Global array repositories and array data search engines. ► Gene Prioritization tools for high-throughput data interpretation. ► Wiki-based community annotation.
Keywords: Bioinformatics; Database; Reproductive genomics; Gametogenesis; Gene prioritization;

Molecular control of oogenesis by Flor Sánchez; Johan Smitz (1896-1912).
Oogenesis is a complex process regulated by a vast number of intra- and extra-ovarian factors. Oogonia, which originate from primordial germ cells, proliferate by mitosis and form primary oocytes that arrest at the prophase stage of the first meiotic division until they are fully-grown. Within primary oocytes, synthesis and accumulation of RNAs and proteins throughout oogenesis are essential for oocyte growth and maturation; and moreover, crucial for developing into a viable embryo after fertilization. Oocyte meiotic and developmental competence is gained in a gradual and sequential manner during folliculogenesis and is related to the fact that the oocyte grows in interaction with its companion somatic cells. Communication between oocyte and its surrounding granulosa cells is vital, both for oocyte development and for granulosa cells differentiation. Oocytes depend on differentiated cumulus cells, which provide them with nutrients and regulatory signals needed to promote oocyte nuclear and cytoplasmic maturation and consequently the acquisition of developmental competence.The purpose of this article is to summarize recent knowledge on the molecular aspects of oogenesis and oocyte maturation, and the crucial role of cumulus–cell interactions, highlighting the valuable contribution of experimental evidences obtained in animal models. This article is part of a Special Issue entitled: Molecular Genetics of Human Reproductive Failure.► Oocyte development depends on several factors expressed pre- and post-natally. ► Oocyte accumulation of transcripts and proteins is essential for oocyte competence. ► EGF-like factors induce cumulus expansion and signaling during oocyte maturation. ► A drop in oocyte cAMP levels post LH stimulus accompanies meiotic resumption. ► Oocyte regulates cumulus cell differentiation and function.
Keywords: Oocyte development; Folliculogenesis; Gene expression; Oocyte maturation; Cumulus–oocyte complex;

Molecular origin of female meiotic aneuploidies by Alan H. Handyside (1913-1920).
Chromosome aneuploidy is a major cause of pregnancy loss, abnormal pregnancy and live births following both natural conception and in vitro fertilisation (IVF) and increases exponentially with maternal age in the decade preceding the menopause. Molecular genetic analysis has shown that these are predominantly maternal in origin and trisomies most frequently occur through errors in the first meiotic division. Analysis of chromosome copy number in the three products of female meiosis, the first and second polar bodies and the corresponding zygote by microarray comparative genomic hybridisation (array CGH), in women of advanced maternal age undergoing IVF, has recently revealed a pattern of frequent multiple meiotic errors, caused by premature predivision of sister chromatids in meiosis I and a high incidence of errors in meiosis II. This pattern is similar to those observed in various mouse models which implicate the gradual depletion of cohesins, which are essential for cohesion of sister chromatids, as the primary cause of age related aneuploidy in female meiosis. However, defects in other aspects of meiosis including the formation and stabilisation of chiasmata and the spindle assembly checkpoint (SAC) may also contribute. The challenge remains to explain the molecular basis of ‘physiological’ rather than ‘chronological’ female ageing and the contribution of multifactorial causes from the fetal to adult ovary. This article is part of a Special Issue entitled: Molecular Genetics of Human Reproductive Failure.► Chromosome aneuploidy is a major cause of pregnancy loss. ► Most aneuploidies arise in female meiosis and increase with maternal age. ► Cohesins are essential for accurate segregation of homologous chromosomes. ► Degradation of cohesins may contribute to the age related increase in aneuploidy.
Keywords: Meiosis; Aneuploidy; Cohesin; Human oocyte; Polar body; Array comparative genomic hybridisation;

Molecular origin of mitotic aneuploidies in preimplantation embryos by Eleni Mantikou; Kai Mee Wong; Sjoerd Repping; Sebastiaan Mastenbroek (1921-1930).
Mitotic errors are common in human preimplantation embryos. The occurrence of mitotic errors is highest during the first three cleavages after fertilization and as a result about three quarters of human preimplantation embryos show aneuploidies and are chromosomally mosaic at day three of development. The origin of these preimplantation mitotic aneuploidies and the molecular mechanisms involved are being discussed in this review.At later developmental stages the mitotic aneuploidy rate is lower. Mechanisms such as cell arrest, apoptosis, active correction of the aneuploidies and preferential allocation of the aneuploid cells to the extra-embryonic tissues could underlie this lower rate.Understanding the mechanisms that cause mitotic aneuploidies in human preimplantation embryos and the way human preimplantation embryos deal with these aneuploidies might lead to ways to limit the occurrence of aneuploidies, in order to ultimately increase the quality of embryos and with that the likelihood of a successful pregnancy in IVF/ICSI. This article is part of a Special Issue entitled: Molecular Genetics of Human Reproductive Failure.► mitotic errors are common in human preimplantation embryos ► especially during the first cleavages after fertilization ► the causes of these mitotic errors are being discussed in this review ► at later developmental stages mitotic aneuploidy rates are lower ► the suggested mechanisms underlying these lower rates are provided
Keywords: Preimplantation embryology; Aneuploidy; Mitosis; In vitro fertilization; Review;

The genomics of the human endometrium by Maria Ruiz-Alonso; David Blesa; Carlos Simón (1931-1942).
The endometrium is a complex tissue that lines the inside of the endometrial cavity. The gene expression of the different endometrial cell types is regulated by ovarian steroids and paracrine-secreted molecules from neighbouring cells. Due to this regulation, the endometrium goes through cyclic modifications which can be divided simply into the proliferative phase, the secretory phase and the menstrual phase. Successful embryo implantation depends on three factors: embryo quality, the endometrium's state of receptivity, and a synchronised dialogue between the maternal tissue and the blastocyst. There is a need to characterise the endometrium's state of receptivity in order to prevent reproductive failure. No single molecular or histological marker for this status has yet been found. Here, we review the global transcriptomic analyses performed in the last decade on a normal human endometrium. These studies provide us with a clue about what global gene expression can be expected for a non-pathological endometrium. These studies have shown endometrial phase-specific transcriptomic profiles and common temporal gene expression patterns. We summarise the biological processes and genes regulated in the different phases of natural cycles and present other works on different conditions as well as a receptivity diagnostic tool based on a specific gene set profile. This article is part of a Special Issue entitled: Molecular Genetics of Human Reproductive Failure.► We review the transcriptomic data on normal human endometrium. ► Single molecule markers cannot classify the status of the endometrium. ► Transcriptomic profiles have proven efficient to classify the endometrial status.
Keywords: Endometrium; Transcriptomic; Menstrual cycle; Receptivity; Infertility;

Molecular aspects of implantation failure by Y.E.M. Koot; G. Teklenburg; M.S. Salker; J.J. Brosens; N.S. Macklon (1943-1950).
Despite expanding global experience with advanced reproductive technologies, the majority of IVF attempts do not result in a successful pregnancy, foremost as a result of implantation failure. The process of embryo implantation, a remarkably dynamic and precisely controlled molecular and cellular event, appears inefficient in humans and is poorly understood. However, insights gained from clinical implantation failure, early pregnancy loss, and emerging techologies that enable molecular interrogation of endometrial–embryo interactions are unravelling this major limiting step in human reproduction. We review current molecular concepts thought to underlie implantation failure, consider the contribution of embryonic and endometrial factors, and discuss the clinical value of putative markers of impaired endometrial receptivity. Finally we highlight the nature of the dialogue between the maternal endometrium and the implanting embryo and discuss the concept of natural embryo selection. This article is part of a Special Issue entitled: Molecular Genetics of Human Reproductive Failure.► Deregulation of evolutionarily conserved gene networks impairs endometrial receptivity. ► In vitro models show that decidualizing endometrial stromal cells recognize embryo quality. ► Emerging model systems should employ gene networks associated with pregnancy failure. ► Data from gene expression studies should be integrated to find markers with clinical value.
Keywords: Implantation failure; IVF; Embryo; Endometrium; Receptivity;

Genetics of early miscarriage by Merel M.J. van den Berg; Merel C. van Maarle; Madelon van Wely; Mariëtte Goddijn (1951-1959).
A miscarriage is the most frequent complication of a pregnancy. Poor chromosome preparations, culture failure, or maternal cell contamination may hamper conventional karyotyping. Techniques such as chromosomal comparative genomic hybridization (chromosomal‐CGH), array-comparative genomic hybridization (array-CGH), fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA) and quantitative fluorescent polymerase chain reaction (QF-PCR) enable us to trace submicroscopic abnormalities. We found the prevalence of chromosome abnormalities in women facing a single sporadic miscarriage to be 45% (95% CI: 38–52; 13 studies, 7012 samples). The prevalence of chromosome abnormalities in women experiencing a subsequent miscarriage after preceding recurrent miscarriage proved to be comparable: 39% (95% CI: 29–50; 6 studies 1359 samples). More chromosome abnormalities are detected by conventional karyotyping compared to FISH or MLPA only (chromosome region specific techniques), and the same amount of abnormalities compared to QF-PCR (chromosome region specific techniques) and chromosomal‐CGH and array-CGH (whole genome techniques) only. Molecular techniques could play a role as an additional technique when culture failure or maternal contamination occurs: recent studies show that by using array-CGH, an additional 5% of submicroscopic chromosome variants can be detected. Because of the small sample size as well as the unknown clinical relevance of these molecular aberrations, more and larger studies should be performed of submicroscopic chromosome abnormalities among sporadic miscarriage samples. For recurrent miscarriage samples molecular technique studies are relatively new. It has often been suggested that miscarriages are due to chromosomal abnormalities in more than 50%, but the present review has determined that chromosomal and submicroscopic genetic abnormalities on average are prevalent in maximally half of the miscarriage samples. This article is part of a Special Issue entitled: Molecular Genetics of Human Reproductive Failure.► Chromosomal genetic abnormalities are prevalent in maximally half of the miscarriage samples. ► Karyotyping can still be used as the gold standard. ► Molecular techniques enable us to detect additional submicroscopic chromosome abnormalities. ► More studies are required to determine the clinical relevance of CNVs.
Keywords: Miscarriage; Recurrent miscarriage; Submicroscopic abnormalities; Molecular genetic abnormalities;

Molecular genetics of preeclampsia and HELLP syndrome — A review by Jiska Jebbink; Astrid Wolters; Febilla Fernando; Gijs Afink; Joris van der Post; Carrie Ris-Stalpers (1960-1969).
Preeclampsia is characterised by new onset hypertension and proteinuria and is a major obstetrical problem for both mother and foetus. Haemolysis elevated liver enzymes and low platelets (HELLP) syndrome is an obstetrical emergency and most cases occur in the presence of preeclampsia. Preeclampsia and HELLP are complicated syndromes with a wide variety in severity of clinical symptoms and gestational age at onset. The pathophysiology depends not only on periconceptional conditions and the foetal and placental genotype, but also on the capability of the maternal system to deal with pregnancy. Genetically, preeclampsia is a complex disorder and despite numerous efforts no clear mode of inheritance has been established. A minor fraction of HELLP cases is caused by foetal homozygous LCHAD deficiency, but for most cases the genetic background has not been elucidated yet. At least 178 genes have been described in relation to preeclampsia or HELLP syndrome. Confined placental mosaicism (CPM) is documented to cause early onset preeclampsia in some cases; the overall contribution of CPM to the occurrence of preeclampsia has not been adequately investigated yet. This article is part of a Special Issue entitled: Molecular Genetics of Human Reproductive Failure.► Both clinically and genetically, preeclampsia is a ‘complex disorder’. ► Over 178 genes have been investigated in relation to preeclampsia. ► Collaboration is needed for adequate power of genetic studies. ► Confined placental mosaicism may be relevant for the genetic basis of preeclampsia.
Keywords: Preeclampsia; HELLP syndrome; IUGR; Pregnancy; Gene;

Tracking fetal development through molecular analysis of maternal biofluids by Andrea G. Edlow; Diana W. Bianchi (1970-1980).
Current monitoring of fetal development includes fetal ultrasonography, chorionic villus sampling or amniocentesis for chromosome analysis, and maternal serum biochemical screening for analytes associated with aneuploidy and open neural tube defects. Over the last 15 years, significant advances in noninvasive prenatal diagnosis (NIPD) via cell-free fetal (cff) nucleic acids in maternal plasma have resulted in the ability to determine fetal sex, RhD genotype, and aneuploidy. Cff nucleic acids in the maternal circulation originate primarily from the placenta. This contrasts with cff nucleic acids in amniotic fluid, which derive from the fetus, and are present in significantly higher concentrations than in maternal blood. The fetal origin of cff nucleic acids in the amniotic fluid permits the acquisition of real-time information about fetal development and gene expression. This review seeks to provide a comprehensive summary of the molecular analysis of cff nucleic acids in maternal biofluids to elucidate mechanisms of fetal development, physiology, and pathology. This article is part of a Special Issue entitled: Molecular Genetics of Human Reproductive Failure.► Cell-free fetal (cff) nucleic acids in maternal plasma originate primarily from the placenta. ► CffDNA permits noninvasive prenatal diagnosis of aneuploidy, single gene disorders, and sex. ► Cff nucleic acids in amniotic fluid originate primarily from the fetus. ► Cff mRNA provides real-time information about fetal functional development.
Keywords: Fetal DNA; Fetal mRNA; Fetal development; Amniotic fluid transcriptome; Pregnancy; Noninvasive prenatal diagnosis;

Purpose. The purpose of this review is to summarize science-based new treatments for human reproductive failure and future developments. Results. First will be discussed popular but erroneous myths of current non-science based treatments. Then will be discussed new treatments and their scientific base, including ovary and egg freezing, and transplantation to preserve fertility in young women undergoing gonadotoxic chemotherapy and radiation for cancer; new perspectives on human epididymal sperm maturation based on a comparison between ICSI (intracytoplasmic sperm injection) with testis sperm versus epididymal sperm; simplifying IVF and reducing cost by more intelligent and milder ovarian stimulation; improving pregnancy rate in older women; searching the genome to find genes which control spermatogenesis and whose deletion or mutation causes spermatogenic failure; and human spermatogenic stem cell culture to treat azoospermia, and to preserve fertility in pre-pubertal boys undergoing cancer treatment. Conclusion. With stem cell biology and molecular understanding of reproductive failure, new therapies for previously untreatable infertility are currently on the near horizon. Conversely our clinical results with new therapeutic approaches are adding to our understanding of the basic science of reproduction. This article is part of a Special Issue entitled: Molecular Genetics of Human Reproductive Failure.► Myths about current popular but erroneous non-science based treatments ► Science-based new fertility therapies for women: ovary, egg freezing; improving IVF ► Human epidiymal sperm maturation ► Sequencing X and Y chromosomes to find genes that control spermatogenesis ► Human spermatogenic stem cell culture: azoospermia treatment, fertility preservation
Keywords: Egg; Ovary; Cryopreservation; ICSI; X and Y chromosomes; Spermatogenic stem cell culture;