A framework for high-resolution phenotyping of candidate male infertility mutants: from human to mouse

Houston, Brendan J; Conrad, Donald F.; O'Bryan, Moira K

doi:10.1007/s00439-020-02159-x

Cited by 43 publications

(26 citation statements)

References 274 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Male sterility is a multifactorial disease with many causes, including anatomic abnormalities, gametogenesis defects, immunological problems, endocrine dysregulations, ejaculatory defects, environmental toxic exposures, and genetic alterations [3]. Genetic abnormalities are known to account for 15-30% of cases, although this number is likely to be considerably underestimated [4,5]. Notably, the molecular functions of many spermatogenic genes remain unknown in vivo [6,7].…”

Section: Introductionmentioning

confidence: 99%

Deficiency of the Tbc1d21 gene causes male infertility with morphological abnormalities of the sperm mitochondria and flagellum in mice

Wang

Chen

et al. 2020

PLoS Genet

Self Cite

View full text Add to dashboard Cite

Approximately 2-15% of couples experience infertility, and around half of these cases are attributed to male infertility. We previously identified TBC1D21 as a sterility-related RabGAP gene derived from infertile men. However, the in vivo function of TBC1D21 in male fertility remains unclear. Here, we show that loss of Tbc1d21 in mice resulted in male infertility, characterized by defects in sperm tail structure and diminished sperm motility. The mitochondria of the sperm-tail had an abnormal irregular arrangement, abnormal diameter, and structural defects. Moreover, the axoneme structure of sperm tails was severely disturbed. Several TBC1D21 interactors were selected via proteomic analysis and functional grouping. Two of the candidate interactors, a subunit protein of translocase in the outer membrane of mitochondria (TOMM20) and an inner arm component of the sperm tail axoneme (Dynein Heavy chain 7, DNAH7), confirmed in vivo physical co-localization with TBC1D21. In addition, TOMM20 and DNAH7 detached and dispersed outside the axoneme in Tbc1d21-deficient sperm, instead of aligning with the axoneme. From a clinical perspective, the transcript levels of TBC1D21 in sperm from teratozoospermia cases were significantly reduced when compared with those in normozoospermia. We concluded that TBC1D21 is critical for mitochondrial and axoneme development of mammalian sperm.

show abstract

Section: Introductionmentioning

confidence: 99%

Deficiency of the Tbc1d21 gene causes male infertility with morphological abnormalities of the sperm mitochondria and flagellum in mice

Wang

Chen

et al. 2020

PLoS Genet

Self Cite

View full text Add to dashboard Cite

show abstract

“…Similar to other medical fields, the major challenge in the monogenic diagnosis of NOA is represented by the attribution of a pathogenic role to the identified variants, especially if they are classified as VUSs. A possible solution of the issue seems to lie in the high-resolution phenotyping of candidate male infertility mouse mutants [ 226 ], thanks to the CRISPR-Cas9 technologies. This approach will indeed allow to overcome the difficulty in interpreting missense variants, demonstrating a cause-effect relationship between a given genotype and NOA phenotype.…”

Section: Discussionmentioning

confidence: 99%

Genetics of Azoospermia

Cioppi

Rosta

Krausz

2021

IJMS

View full text Add to dashboard Cite

Azoospermia affects 1% of men, and it can be due to: (i) hypothalamic-pituitary dysfunction, (ii) primary quantitative spermatogenic disturbances, (iii) urogenital duct obstruction. Known genetic factors contribute to all these categories, and genetic testing is part of the routine diagnostic workup of azoospermic men. The diagnostic yield of genetic tests in azoospermia is different in the different etiological categories, with the highest in Congenital Bilateral Absence of Vas Deferens (90%) and the lowest in Non-Obstructive Azoospermia (NOA) due to primary testicular failure (~30%). Whole-Exome Sequencing allowed the discovery of an increasing number of monogenic defects of NOA with a current list of 38 candidate genes. These genes are of potential clinical relevance for future gene panel-based screening. We classified these genes according to the associated-testicular histology underlying the NOA phenotype. The validation and the discovery of novel NOA genes will radically improve patient management. Interestingly, approximately 37% of candidate genes are shared in human male and female gonadal failure, implying that genetic counselling should be extended also to female family members of NOA patients.

show abstract

“…Similar to DSD, next generation sequencing technologies have improved the detection of putative genetic mutations associated with infertility, but the exact link between genotype and phenotype is unclear for most cases. Rodent models are still the gold standard used to correlate the genotype and phenotype in male (in)fertility [ 187 ]. Single-cell -omics applied to mouse models has been used to efficiently characterize the cellular and molecular bases of male and female infertility.…”

Section: Single-cell -Omics In Gonadal Diseasementioning

confidence: 99%

Applying Single-Cell Analysis to Gonadogenesis and DSDs (Disorders/Differences of Sex Development)

Estermann

Smith

2020

IJMS

View full text Add to dashboard Cite

The gonads are unique among the body’s organs in having a developmental choice: testis or ovary formation. Gonadal sex differentiation involves common progenitor cells that form either Sertoli and Leydig cells in the testis or granulosa and thecal cells in the ovary. Single-cell analysis is now shedding new light on how these cell lineages are specified and how they interact with the germline. Such studies are also providing new information on gonadal maturation, ageing and the somatic-germ cell niche. Furthermore, they have the potential to improve our understanding and diagnosis of Disorders/Differences of Sex Development (DSDs). DSDs occur when chromosomal, gonadal or anatomical sex are atypical. Despite major advances in recent years, most cases of DSD still cannot be explained at the molecular level. This presents a major pediatric concern. The emergence of single-cell genomics and transcriptomics now presents a novel avenue for DSD analysis, for both diagnosis and for understanding the molecular genetic etiology. Such -omics datasets have the potential to enhance our understanding of the cellular origins and pathogenesis of DSDs, as well as infertility and gonadal diseases such as cancer.

show abstract

A framework for high-resolution phenotyping of candidate male infertility mutants: from human to mouse

Cited by 43 publications

References 274 publications

Deficiency of the Tbc1d21 gene causes male infertility with morphological abnormalities of the sperm mitochondria and flagellum in mice

Deficiency of the Tbc1d21 gene causes male infertility with morphological abnormalities of the sperm mitochondria and flagellum in mice

Genetics of Azoospermia

Applying Single-Cell Analysis to Gonadogenesis and DSDs (Disorders/Differences of Sex Development)

Contact Info

Product

Resources

About