Background Infertility is a major issue in human reproductive health, affecting an estimated 15% of couples worldwide. Infertility can result from disorders of sex development (DSD) or from reproductive endocrine disorders (REDs) with onset in infancy, early childhood or adolescence. Male infertility, accounting for roughly half of all infertility cases, generally manifests as decreased sperm count (azoospermia or oligozoospermia), attenuated sperm motility (asthenozoospermia) or a higher proportion of morphologically abnormal sperm (teratozoospermia). Female infertility can be divided into several classical types, including, but not limited to, oocyte maturation arrest, premature ovarian insufficiency (POI), fertilization failure and early embryonic arrest. An estimated one half of infertility cases have a genetic component; however, most genetic causes of human infertility are currently uncharacterized. The advent of high-throughput sequencing technologies has greatly facilitated the identification of infertility-associated gene mutations in patients over the past 20 years. Objective and rationale This review aims to conduct a narrative review of the genetic causes of human infertility. Loss-of-function mutation discoveries related to human infertility are summarized and further illustrated in tables. Corresponding knockout/mutated animal models of causative genes for infertility are also introduced. Search methods A search of the PubMed database was performed to identify relevant studies published in English. The term 'mutation' was combined with a range of search terms related to the core focus of the review: infertility, DSD, REDs, azoospermia or oligozoospermia, asthenozoospermia, multiple morphological abnormalities of the sperm flagella (MMAF), primary ciliary dyskinesia (PCD), acephalic spermatozoa syndrome (ASS), globozoospermia, teratozoospermia, acrosome, oocyte maturation arrest, POI, zona pellucida, fertilization defects and early embryonic arrest. Outcomes Our search generated ∼2000 records. Overall, 350 articles were included in the final review. For genetic investigation of human infertility, the traditional candidate gene approach is proceeding slowly, whereas high-throughput sequencing technologies in larger cohorts of individuals is identifying an increasing number of causative genes linked to human infertility. This review provides a wide panel of gene mutations in several typical forms of human infertility, including DSD, REDs, male infertility (oligozoospermia, MMAF, PCD, ASS and globozoospermia) and female infertility (oocyte maturation arrest, POI, fertilization failure and early embryonic arrest). The causative genes, their identified mutations, mutation rate, studied population and their corresponding knockout/mutated mice of non-obstructive azoospermia, MMAF, ASS, globozoospermia, oocyte maturation arrest, POI, fertilization failure and early embryonic arrest are further illustrated by tables. In this review, we suggest that (i) our current knowledge of infertility is largely obtained from knockout mouse models; (ii) larger cohorts of clinical cases with distinct clinical characteristics need to be recruited in future studies; (iii) the whole picture of genetic causes of human infertility relies on both the identification of more mutations for distinct types of infertility and the integration of known mutation information; (iv) knockout/mutated animal models are needed to show whether the phenotypes of genetically altered animals are consistent with findings in human infertile patients carrying a deleterious mutation of the homologous gene; and (v) the molecular mechanisms underlying human infertility caused by pathogenic mutations are largely unclear in most current studies. Wilder implications It is important to use our current understanding to identify avenues and priorities for future research in the field of genetic causes of infertility as well as to apply mutation knowledge to risk prediction, genetic diagnosis and potential treatment for human infertility.

Molecular genetics of infertility: loss-of-function mutations in humans and corresponding knockout/mutated mice

Fluorescence- and magnetic-activated cell sorting strategies to isolate and enrich human spermatogonial stem cells.

Genome editing tools have revolutionized the generation of genetically modified animals including livestock. In particular, the domestic pig is a proven model of human physiology and an agriculturally important species. In this study, we utilized the CRISPR/Cas9 system to edit the NANOS2 gene in pig embryos to generate offspring with mono-allelic and bi-allelic mutations. We found that NANOS2 knockout pigs phenocopy knockout mice with male specific germline ablation but other aspects of testicular development are normal. Moreover, male pigs with one intact NANOS2 allele and female knockout pigs are fertile. From an agriculture perspective, NANOS2 knockout male pigs are expected to serve as an ideal surrogate for transplantation of donor spermatogonial stem cells to expand the availability of gametes from genetically desirable sires.

Generation of germline ablated male pigs by CRISPR/Cas9 editing of the NANOS2 gene

The RNA-binding proteins of the Nanos family play an essential role in germ cell development and survival in a wide range of metazoan species. They function by suppressing the expression of target mRNAs through the recruitment of effector complexes, which include the CCR4–NOT deadenylase complex. Here, we show that the three human Nanos paralogs (Nanos1–3) interact with the CNOT1 C-terminal domain and determine the structural basis for the specific molecular recognition. Nanos1–3 bind CNOT1 through a short CNOT1-interacting motif (NIM) that is conserved in all vertebrates and some invertebrate species. The crystal structure of the human Nanos1 NIM peptide bound to CNOT1 reveals that the peptide opens a conserved hydrophobic pocket on the CNOT1 surface by inserting conserved aromatic residues. The substitutions of these aromatic residues in the Nanos1–3 NIMs abolish binding to CNOT1 and abrogate the ability of the proteins to repress translation. Our findings provide the structural basis for the recruitment of the CCR4–NOT complex by vertebrate Nanos, indicate that the NIMs are the major determinants of the translational repression mediated by Nanos, and identify the CCR4–NOT complex as the main effector complex for Nanos function.

/pdf/structural-basis-for-the-nanos-mediated-recruitment-of-the-zoxjilqhdz.pdf

Structural basis for the Nanos-mediated recruitment of the CCR4–NOT complex and translational repression

Genetic anomalies are known to affect about 15% of infertile patients with azoospermia or severe oligozoospermia. Despite a throughout diagnostic work-up, in up to the 72% of the male partners of infertile couples, no etiological factor can be found; hence, the cause of infertility remains unclear. Recently, several novel genetic causes of spermatogenic failure (SPGF) have been described. The aim of this review was to collect all the available evidence of SPGF genetics, matching data from in-vitro and animal models with those in human beings to provide a comprehensive and updated overview of the genes capable of affecting spermatogenesis. By reviewing the literature, we provided a list of 60 candidate genes for SPGF. Their investigation by Next Generation Sequencing in large cohorts of patients with apparently idiopathic infertility would provide new interesting data about their racial- and ethnic-related prevalence in infertile patients, likely raising the diagnostic yields. We propose a phenotype-based approach to identify the genes to look for.

New insights into the genetics of spermatogenic failure: a review of the literature.

The highly conserved Nanos gene was found to encode a translational repressor necessary for germ-cell development in lower organisms. The mammalian homologue, Nanos2, was recently found to be expressed in the mouse germ cells. Since its disruption caused infertility exclusively in males, we sought to study the significance of this gene in human male reproduction. Here, we describe for the first time the expression pattern of the NANOS2 gene in human tissues and show that it is testis specific. We found that NANOS2 protein is present in prenatal germ cells and at later stages in spermatogenesis. To elucidate the role of NANOS2 in human germ-line development, we screened this gene for mutations in 214 males with isolated sterility and spermatogenic abnormalities. We ident- ified two heterozygous variants, each in a different oligospermic patient, the second allele being the wild-type. The influence of the first variant, a missense mutation H68Q on the sterility phenotype, was not obvious since it was accompanied by a microdeletion within the AZF region of the Y chromosome. The second variant contained a silent mutation, H109H. Although both mutations were situated within the most conserved RNA-binding domain and were absent in 400 fertile males, it is not obvious that they cause male infertility.

/pdf/the-highly-conserved-nanos2-protein-testis-specific-3j4rr8hg89.pdf

The highly conserved NANOS2 protein: testis-specific expression and significance for the human male reproduction

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

L. Tomczyk

Author Tools

Chat about Author

Papers

The highly conserved NANOS2 protein: testis-specific expression and significance for the human male reproduction