Genetic Basis of Oligozoospermia in Infertile Males

Summary

Principal Investigator: Alexander N Yatsenko
Abstract: DESCRIPTION (provided by applicant): The applicant is a clinical molecular geneticist who is eligible for ABMG-accredited certification in the Clinical Molecular Genetics program. His long-term objective is to become an independent physician- scientist focused on studying the genetic bases of male infertility that affects the reproductive health of men. This proposal will provide the applicant with training in reproductive biology and new technologies in human and mouse genetics. The overall scientific goal of this project is to identify and characterize mutations in male infertility- associated genes that result in oligozoospermia (OS). Male infertility affects nearly 4,000,000 men in the USA, of which at least 25% are diagnosed as idiopathic. An etiology of male infertility is often associated with abnormal semen characteristics (i.e., sperm concentration, motility, morphology, etc.). Oligozoospermia is the most common semen abnormality observed among infertile males. The Specific Aims of the proposed study are: 1) Develop cDNA and DNA collections of oligozoospermic semen samples;2) Study candidate genes for OS-associated mutations by direct cDNA sequencing and in vitro functional assays;3) Identify and map genomic aberrations associated with severe OS, using oligo microarray comparative genome hybridization (CGH) technology;and 4) Characterize the CGH-detected gene-candidate that is associated with OS, using mouse knockout or knock-in models. The selection of OS-associated candidate genes will be prioritized according to their protein functional evidence and the gene's position in altered chromosome region. The applicant will study mutations and genomic abnormalities in cDNA and DNA samples from oligozoospermic patients, using cDNA sequencing approach and comprehensive genome-wide CGH microarray. A mutant mouse model will be developed in attempt to mimic the most common form of semen abnormality, oligozoospermia in human. The candidate will characterize the mutant mice by determining the spatiotemporal effects of gene ablation on spermatogenesis and fertilization. Identification and characterization specific gene mutations that associate with oligozoospermia will lead to the development of novel diagnostic procedures, and will help with prognosis in assisted reproductive medicine. Ultimately, it will provide insight into the molecular basis of male infertility, and eventually may facilitate the creation of non-hormonal contraceptives. Proposed study will be performed in an environment known for its collaborative studies in human and mouse genetics. The long-term career goals of the applicant is to become an independent physician-scientist focused on studying genetic disorders that affect male reproductive system.
Funding Period: 2010-05-06 - 2015-04-30
more information: NIH RePORT

Top Publications

  1. pmc The power of mouse genetics to study spermatogenesis
    A N Yatsenko
    Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA
    J Androl 31:34-44. 2010
  2. pmc Comprehensive 5-year study of cytogenetic aberrations in 668 infertile men
    Alexander N Yatsenko
    Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, USA
    J Urol 183:1636-42. 2010
  3. pmc Mendelian genetics of male infertility
    Kathleen Hwang
    Scott Department of Urology, Baylor College of Medicine, Houston, TX, USA
    Ann N Y Acad Sci 1214:E1-E17. 2010
  4. pmc Association of mutations in the zona pellucida binding protein 1 (ZPBP1) gene with abnormal sperm head morphology in infertile men
    Alexander N Yatsenko
    Departments of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA
    Mol Hum Reprod 18:14-21. 2012
  5. pmc UBE2B mRNA alterations are associated with severe oligozoospermia in infertile men
    Alexander N Yatsenko
    Department of OBGYN, School of Medicine, University of Pittsburgh, PA 15213, USA
    Mol Hum Reprod 19:388-94. 2013

Detail Information

Publications7

  1. pmc The power of mouse genetics to study spermatogenesis
    A N Yatsenko
    Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA
    J Androl 31:34-44. 2010
    ..Ultimately, basic advances in mammalian nonhuman reproduction will translate to clinical advances in human reproduction and testing for infertile humans, thereby helping to improve diagnostics and health care for infertile patients...
  2. pmc Comprehensive 5-year study of cytogenetic aberrations in 668 infertile men
    Alexander N Yatsenko
    Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, USA
    J Urol 183:1636-42. 2010
    ..To refine the incidence and nature of chromosomal aberrations in males with infertility we reviewed cytogenetic results in 668 infertile men with oligozoospermia and azoospermia...
  3. pmc Mendelian genetics of male infertility
    Kathleen Hwang
    Scott Department of Urology, Baylor College of Medicine, Houston, TX, USA
    Ann N Y Acad Sci 1214:E1-E17. 2010
    ....
  4. pmc Association of mutations in the zona pellucida binding protein 1 (ZPBP1) gene with abnormal sperm head morphology in infertile men
    Alexander N Yatsenko
    Departments of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA
    Mol Hum Reprod 18:14-21. 2012
    ..We hypothesize that missense mutations exert a dominant-negative effect due to altered ZPBP1 protein folding and protein:protein interactions in the acrosome...
  5. pmc UBE2B mRNA alterations are associated with severe oligozoospermia in infertile men
    Alexander N Yatsenko
    Department of OBGYN, School of Medicine, University of Pittsburgh, PA 15213, USA
    Mol Hum Reprod 19:388-94. 2013
    ..We speculate that the contribution of post-transcriptional mRNA defects to oligozoospermia could be greater than previously anticipated...

Research Grants30

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    KLAUS MICHAEL HAHN; Fiscal Year: 2013
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  2. Expanding Excellence in Developmental Biology in Oklahoma
    Linda F Thompson; Fiscal Year: 2013
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  3. The evolutionary and molecular mechanisms underlying sperm performance in an emer
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  4. The MRAD9 Radioresistance Gene
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  5. Stanford University Center for Reproductive and Stem Cell biology
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  6. Center for Reproductive Science and Medicine
    Pamela L Mellon; Fiscal Year: 2013
    ..The SCCPIR Human Ovary Tissue Bank provides tissue to NIH-funded investigators nation-wide. ..
  7. Molecular Analyses and Interventions for Biodefense and Emerging Pathogens
    Olaf Schneewind; Fiscal Year: 2013
    ..Research and training at the GLRCE is governed by a mechanism involving ongoing review of scientific excellence and translational goals, inter-institutional advisory boards and external scientific advisory bodies. ..
  8. Semi-volatile PCBs: Sources, Exposures, Toxicities
    Larry W Robertson; Fiscal Year: 2013
    ..These data and dietary studies in the last Aim will provide a scientific basis for risk assessment and advice for stakeholders with the ultimate goal to protect highly-exposed individuals and populations. ..