Modeling human male infertility in mice

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DESCRIPTION (provided by applicant): An estimated 15% of couples are affected by infertility worldwide. Males and females contribute roughly equally to infertility. The regulation of fertility is clearly complex, as more than 200 knockout mice have been described to have infertility as a major phenotype. Despite progress made in mouse models, few genetic causes of male infertility in humans have been identified. The slow progress in the study of genetic causes of infertility in humans can be attributed to two factors: 1) causative mutations in a particular gene are expected to be extremely rare; and 2) causality is nearly impossible to prove, as traditional pedigree-based linkage analysis is not applicable, due to the lack of offspring caused by infertility. Clearly new approaches are required to investigate genetic causes of human infertility. Accordingly, we propose that the most informative way to advance our knowledge of human male infertility is to utilize knockin technology to generate and characterize mice that harbor the analogous human mutation. We have recently demonstrated that TAF7L, an X chromosome-encoded transcription factor, plays a critical role in sperm production in mice. To determine if TAF7L could also play a role in human infertility, we screened >100 infertile men and identified a single amino acid substitution (D?G) in TAF7L in an infertile man with low sperm count. Our yeast genetic studies demonstrated that this conserved aspartic residue is required for the function of TAF7, yeast homologue of TAF7L. To definitively determine if it plays a causative role in male infertility, we will express the analogous mutation in knockin mice such that only the mutated TAF7L is expressed. If a single point mutation in TAF7L is indeed sufficient to reduce male fertility, it will represent the first identified single gene mutation to play a causative role in male infertility in humans. The significance of such a finding will be two-fold. First, TAF7L mutations could be maternally inherited and should be considered in genetic counseling: since this is an X- linked gene, a single mutation would render males sterile. Second, as TAF7L is a transcription factor, future studies to determine protein-protein interactions affected by this mutation could provide significant insight into the unique transcription programs in germ cells. PUBLIC HEALTH RELEVANCE: Infertility is a widespread reproductive health problem affecting millions of couples in the US. Completion of this project will identify the genetic cause of some cases of male infertility in humans.