scholarly journals Novel Bi-Allelic Variants of FANCM Cause Sertoli Cell-Only Syndrome and Non-Obstructive Azoospermia

2021 ◽  
Vol 12 ◽  
Author(s):  
Yuxiang Zhang ◽  
Peng Li ◽  
Nachuan Liu ◽  
Tao Jing ◽  
Zhiyong Ji ◽  
...  
Keyword(s):  
Male Infertility ◽  
Sertoli Cell ◽  
Severe Disease ◽  
Sporadic Case ◽  
Compound Heterozygous ◽  
Obstructive Azoospermia ◽  
Core Complex ◽  
Allelic Variants ◽  
Interstrand Crosslink ◽  
Compound Heterozygous Variants

Non-obstructive azoospermia (NOA) is the most severe disease in male infertility, but the genetic causes for the majority of NOA remain unknown. FANCM is a member of Fanconi Anemia (FA) core complex, whose defects are associated with cell hypersensitivity to DNA interstrand crosslink (ICL)-inducing agents. It was reported that variants in FANCM (MIM: 609644) might cause azoospermia or oligospermia. However, there is still a lack of evidence to explain the association between different FANCM variants and male infertility phenotypes. Herein, we identified compound heterozygous variants in FANCM in two NOA-affected brothers (c. 1778delG:p. R593Qfs*76 and c. 1663G > T:p. V555F), and a homozygous variant in FANCM (c. 1972C > T:p. R658X) in a sporadic case with NOA, respectively. H&E staining and immunohistochemistry showed Sertoli cell-only Syndrome (SCOS) in the three patients with NOA. Collectively, our study expands the knowledge of variants in FANCM, and provides a new insight to understand the genetic etiology of NOA.

scholarly journals Mutations in the stromal antigen 3 (STAG3) gene cause male infertility due to meiotic arrest

2019 ◽  
Author(s):  
N van der Bijl ◽  
A Röpke ◽  
U Biswas ◽  
M Wöste ◽  
R Jessberger ◽  
...  
Keyword(s):  
Male Infertility ◽  
Germ Cells ◽  
Protein Function ◽  
Sanger Sequencing ◽  
Compound Heterozygous ◽  
Sequence Variants ◽  
Coding Region ◽  
Meiotic Arrest ◽  
Healthy Human ◽  
Compound Heterozygous Variants

Abstract STUDY QUESTION Are sequence variants in the stromal antigen 3 (STAG3) gene a cause for non-obstructive azoospermia (NOA) in infertile human males? SUMMARY ANSWER Sequence variants affecting protein function of STAG3 cause male infertility due to meiotic arrest. WHAT IS KNOWN ALREADY In both women and men, STAG3 encodes for a meiosis-specific protein that is crucial for the functionality of meiotic cohesin complexes. Sequence variants in STAG3 have been reported to cause meiotic arrest in male and female mice and premature ovarian failure in human females, but not in infertile human males so far. STUDY DESIGN, SIZE, DURATION The full coding region of STAG3 was sequenced directly in a cohort of 28 men with NOA due to meiotic arrest. In addition, a larger group of 275 infertile men that underwent whole-exome sequencing (WES) was screened for potential STAG3 sequence variants. Furthermore, meiotic spreads, immunohistochemistry, WES and population sampling probability (PSAP) have been conducted in the index case. PARTICIPANTS/MATERIALS, SETTING, METHODS This study included 28 infertile but otherwise healthy human males who underwent Sanger sequencing of the full coding region of STAG3. Additionally, WES data of 275 infertile human males with different infertility phenotypes have been screened for relevant STAG3 variants. All participants underwent karyotype analysis and azoospermia factor (AZF) screening in advance. In the index patient, segregation analysis, WES data, PSAP, lab parameters, testis histology and nuclear spreads have been added to suplort the findings. MAIN RESULTS AND THE ROLE OF CHANCE Two compound-heterozygous variants in STAG3 (c.[1262T>G];[1312C>T], p.[(Leu421Arg)];[(Arg438Ter)]) have been found to cause male infertility due to complete bilateral meiotic arrest in an otherwise healthy human male. Compound heterozygosity was confirmed by Sanger sequencing of the parents and the patient’s brother. Other variants which may affect spermatogenesis have been ruled out through analysis of the patient’s WES data and application of the PSAP pipeline. As expected from Stag3 knockout-mice meiotic spreads, germ cells did not develop further than zygotene and showed drastic chromosome aberrations. No rare variants in STAG3 were found in the 275 infertile males with other phenotypes. Our results indicate that STAG3 variants that negatively affect its protein function are a rare cause of NOA (<1% of cases). LIMITATIONS, REASONS FOR CAUTION We identified only one patient with compound-heterozygous variants in STAG3 causing NOA due to meiotic arrest. Future studies should evaluate STAG3 variants in larger cohorts to support this finding. WIDER IMPLICATIONS OF THE FINDINGS Identification of STAG3 sequence variants in infertile human males should improve genetic counselling as well as diagnostics and treatment. Especially before testicular sperm extraction (TESE) for ICSI, STAG3 variants should be ruled out to prevent unnecessary interventions with frustrating outcomes for both patients and clinicians. STUDY FUNDING/COMPETING INTEREST(S) This work was carried out within the frame of the German Research Foundation (DFG) Clinical Research Unit ‘Male Germ Cells: from Genes to Function’ (CRU326). Work in the laboratory of R.J. is supported by a grant of the European Union H2020 program GermAge. The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER Not applicable.

scholarly journals Bi-allelic variants in human WDR63 cause male infertility via abnormal inner dynein arms assembly

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Shuai Lu ◽  
Yayun Gu ◽  
Yifei Wu ◽  
Shenmin Yang ◽  
Chenmeijie Li ◽  
...  
Keyword(s):  
Male Infertility ◽  
Protein Complex ◽  
Molecular Mechanisms ◽  
Obstructive Azoospermia ◽  
Loss Of Function ◽  
Allelic Variants ◽  
Transmission Electron ◽  
Repeat Domain ◽  
Dynein Arms ◽  
Cilia And Flagella

AbstractInner dynein arm (IDA), composed of a series of protein complex, is necessary to cilia and flagella bend formation and beating. Previous studies indicated that defects of IDA protein complex result in multiple morphological abnormalities of the sperm flagellum (MMAF) and male infertility. However, the genetic causes and molecular mechanisms in the IDAs need further exploration. Here we identified two loss-of-function variants of WDR63 in both MMAF and non-obstructive azoospermia (NOA) affected cohorts. WDR63 encodes an IDA-associated protein that is dominantly expressed in testis. We next generated Wdr63-knockout (Wdr63-KO) mice through the CRISPR-Cas9 technology. Remarkably, Wdr63-KO induced decreased sperm number, abnormal flagellar morphology and male infertility. In addition, transmission electron microscopy assay showed severely disorganized “9 + 2” axoneme and absent inner dynein arms in the spermatozoa from Wdr63-KO male mice. Mechanistically, we found that WDR63 interacted with WDR78 mainly via WD40-repeat domain and is necessary for IDA assembly. Furthermore, WDR63-associated male infertility in human and mice could be overcome by intracytoplasmic sperm injection (ICSI) treatment. In conclusion, the present study demonstrates that bi-allelic variants of WDR63 cause male infertility via abnormal inner dynein arms assembly and flagella formation and can be used as a genetic diagnostic indicator for infertility males.

scholarly journals Association of DNAH11 gene polymorphisms with asthenozoospermia in Northeast Chinese patients

2019 ◽  
Vol 39 (6) ◽  
Author(s):  
Dongliang Zhu ◽  
Hongguo Zhang ◽  
Ruixue Wang ◽  
Xiaojun Liu ◽  
Yuting Jiang ◽  
...  
Keyword(s):  
Male Infertility ◽  
Heavy Chain ◽  
In Silico Analysis ◽  
Chinese Patients ◽  
Compound Heterozygous ◽  
Respiratory Cilia ◽  
Increased Risk ◽  
Compound Heterozygous Variants ◽  
Targeted Gene Sequencing ◽  
High Degree

Abstract Summary: Reduced or no progressive sperm motility in the fresh ejaculate defines asthenozoospermia as one of the major causes of male infertility. The axonemal heavy chain dynein type 11 (DNAH11) gene encodes for one of the axonemal dynein heavy chain (DHC) family members and participates in assembling respiratory cilia and sperm flagella. Given the high degree of conservation of DNAH11, mutations could give rise to primary ciliary dyskinesia (PCD) and asthenozoospermia. To date, few studies have reported on the association between variants in DNAH11 and asthenozoospermia. In the present study, 87 patients with idiopathic asthenozoospermia for variants in DNAH11 were screened by using high-throughput targeted gene sequencing technology. Bioinformatics analysis was further assessed. We found compound heterozygous variants (c.9484-1 G>T, c.12428 T>C) of DNAH11 detected in 1 of 87 patients. The variant c.9484-1 G>T was confirmed as a novel virulence variant which was predicted to affect splicing by Human Splicing Finder 3.1. And c.12428 T>C was predicted to be mildly pathogenic in silico analysis. We found that DNAH11 polymorphisms display strong associations with asthenozoospermia, and may contribute to an increased risk of male infertility in Chinese patients.

scholarly journals Novel ARG1 variants identified in a patient with arginase 1 deficiency

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Katsuyuki Yokoi ◽  
Yoko Nakajima ◽  
Toshihiro Yasui ◽  
Makoto Yoshino ◽  
Tetsushi Yoshikawa ◽  
...  
Keyword(s):  
Sanger Sequencing ◽  
Arginase Activity ◽  
Compound Heterozygous ◽  
Measurement Sensitivity ◽  
Protein Core ◽  
Arginase 1 ◽  
Conserved Domain ◽  
New Variant ◽  
Compound Heterozygous Variants

AbstractWe report a case of a 13-year-old boy with arginase 1 deficiency carrying a new variant in ARG1. Sanger sequencing identified the compound heterozygous variants: NM_000045.4: c.365G>A (p.Trp122*)/c.820G>A (p.Asp274Asn). Although not previously reported, the p.Asp274Asn variant is predicted to have strong pathogenicity because it is located in a highly conserved domain in the protein core and arginase activity in the patient was below measurement sensitivity.

scholarly journals Compound heterozygous variants in LAMC3 in association with posterior periventricular nodular heterotopia

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Carla De Angelis ◽  
Alicia B. Byrne ◽  
Rebecca Morrow ◽  
Jinghua Feng ◽  
Thuong Ha ◽  
...  
Keyword(s):  
Cortical Development ◽  
Occipital Cortex ◽  
Compound Heterozygous ◽  
Valuable Insight ◽  
Periventricular Nodular Heterotopia ◽  
Case Presentation ◽  
Malformation Of Cortical Development ◽  
Nodular Heterotopia ◽  
Compound Heterozygous Variants ◽  
Insight Into

Abstract Background Periventricular nodular heterotopia (PNH) is a malformation of cortical development characterized by nodules of abnormally migrated neurons. The cause of posteriorly placed PNH is not well characterised and we present a case that provides insights into the cause of posterior PNH. Case presentation We report a fetus with extensive posterior PNH in association with biallelic variants in LAMC3. LAMC3 mutations have previously been shown to cause polymicrogyria and pachygyria in the occipital cortex, but not PNH. The occipital location of PNH in our case and the proposed function of LAMC3 in cortical development suggest that the identified LAMC3 variants may be causal of PNH in this fetus. Conclusion We hypothesise that this finding extends the cortical phenotype associated with LAMC3 and provides valuable insight into genetic cause of posterior PNH.

scholarly journals Cellular Therapy via Spermatogonial Stem Cells for Treating Impaired Spermatogenesis, Non-Obstructive Azoospermia

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1779
Author(s):  
Nesma E. Abdelaal ◽  
Bereket Molla Tanga ◽  
Mai Abdelgawad ◽  
Sahar Allam ◽  
Mostafa Fathi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Male Infertility ◽  
Cellular Therapy ◽  
Antihypertensive Drugs ◽  
Testicular Biopsy ◽  
Testicular Tissue ◽  
Spermatogonial Stem Cells ◽  
Obstructive Azoospermia ◽  
Promising Alternative ◽  
Major Health Problem

Male infertility is a major health problem affecting about 8–12% of couples worldwide. Spermatogenesis starts in the early fetus and completes after puberty, passing through different stages. Male infertility can result from primary or congenital, acquired, or idiopathic causes. The absence of sperm in semen, or azoospermia, results from non-obstructive causes (pretesticular and testicular), and post-testicular obstructive causes. Several medications such as antihypertensive drugs, antidepressants, chemotherapy, and radiotherapy could lead to impaired spermatogenesis and lead to a non-obstructive azoospermia. Spermatogonial stem cells (SSCs) are the basis for spermatogenesis and fertility in men. SSCs are characterized by their capacity to maintain the self-renewal process and differentiation into spermatozoa throughout the male reproductive life and transmit genetic information to the next generation. SSCs originate from gonocytes in the postnatal testis, which originate from long-lived primordial germ cells during embryonic development. The treatment of infertility in males has a poor prognosis. However, SSCs are viewed as a promising alternative for the regeneration of the impaired or damaged spermatogenesis. SSC transplantation is a promising technique for male infertility treatment and restoration of spermatogenesis in the case of degenerative diseases such as cancer, radiotherapy, and chemotherapy. The process involves isolation of SSCs and cryopreservation from a testicular biopsy before starting cancer treatment, followed by intra-testicular stem cell transplantation. In general, treatment for male infertility, even with SSC transplantation, still has several obstacles. The efficiency of cryopreservation, exclusion of malignant cells contamination in cancer patients, and socio-cultural attitudes remain major challenges to the wider application of SSCs as alternatives. Furthermore, there are limitations in experience and knowledge regarding cryopreservation of SSCs. However, the level of infrastructure or availability of regulatory approval to process and preserve testicular tissue makes them tangible and accurate therapy options for male infertility caused by non-obstructive azoospermia, though in their infancy, at least to date.

scholarly journals Mevalonate Kinase-Associated Diseases: Hunting for Phenotype–Genotype Correlation

2021 ◽  
Vol 10 (8) ◽  
pp. 1552
Author(s):  
Guilaine Boursier ◽  
Cécile Rittore ◽  
Florian Milhavet ◽  
Laurence Cuisset ◽  
Isabelle Touitou
Keyword(s):  
Severe Disease ◽  
Compound Heterozygous ◽  
Mevalonate Kinase ◽  
Kinase Gene ◽  
New Associations ◽  
Associated Diseases ◽  
Ocular Symptoms ◽  
Disseminated Superficial Actinic Porokeratosis ◽  
Increased Risk ◽  
Genotype Correlation

Mevalonate kinase-associated diseases (MKAD) are caused by pathogenic mutations in the mevalonate kinase gene (MVK) and encompass several phenotypically different rare and hereditary autoinflammatory conditions. The most serious is a recessive systemic metabolic disease called mevalonic aciduria, and the most recently recognized is disseminated superficial actinic porokeratosis, a dominant disease limited to the skin. To evaluate a possible correlation between genotypes and (1) the different MKAD clinical subtypes or (2) the occurrence of severe manifestations, data were reviewed for all patients with MVK variants described in the literature (N = 346), as well as those referred to our center (N = 51). The genotypes including p.(Val377Ile) (homozygous or compound heterozygous) were more frequent in mild systemic forms but were also sometimes encountered with severe disease. We confirmed that amyloidosis was more prevalent in patients compound heterozygous for p.(Ile268Thr) and p.(Val377Ile) than in others and revealed new associations. Patients homozygous for p.(Leu264Phe), p.(Ala334Thr) or compound heterozygous for p.(His20Pro) and p.(Ala334Thr) had increased risk of severe neurological or ocular symptoms. All patients homozygous for p.(Leu264Phe) had a cataract. The variants associated with porokeratosis were relatively specific and more frequently caused a frameshift than in patients with other clinical forms (26% vs. 6%). We provide practical recommendations focusing on phenotype–genotype correlation in MKAD that could be helpful for prophylactic management.

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