Unique infertility-causing mutation
JAX® NOTES Issue 512, Winter 2008
Approximately 15% of all couples, regardless of ethnic background, experience infertility. Given the tremendous progress in biomedical research, why is human infertility such a persistent problem? Because we know very little about the genes that regulate the complex process of human reproduction. For example, though an estimated 2,000 genes are involved just in orchestrating human spermatogenesis, few of them have been identified. Additionally, few families that pass on discrete infertility alleles have been identified, and infertility can have complex and seemingly contradictory causes. To this day, most of the progress in understanding the genetics of human infertility has come from studies in laboratory mice. Recently, mice have given us one more clue — through the efforts of a research team that included JAX Professor John Eppig, JAX Senior Research Scientist MaryAnn Handel, and a Cornell University group led by adjunct JAX scientist Dr. John Schimenti. The team reported that a recessive point mutation in a gene encoding the regulatory protein bromodomain and WD repeat domain containing 1 (BRWD1), part of a protein family involved in a variety of functions, including transcription, chromatin remodeling, and DNA regulation, affects gametogenesis in both sexes of mice (Philipps et al. 2008).
The mice used in the study were produced as part of a large-scale "ReproGenomics" program at The Jackson Laboratory, a program that has generated scores of new infertility models by ethylnitrosourea (N-Ethyl-N-nitrosourea or ENU) germline mutagenesis (JAX® NOTES 2007). Although homozygotes for the new-found mutation are phenotypically normal, they are infertile: the females produce few oocytes that progress to metaphase II (MII), and none that progress beyond the two pronuclei stage, the males produce few sperm. The mutation in these mice is unique because it affects different germ cell stages in each sex. Most mutations that cause infertility in both sexes disrupt fundamental processes in meiosis I. These processes do not appear to be affected in these mutants. Instead, the males are infertile because they produce few sperm, and the females are infertile because their oocytes don't mature. The implication is that there is a novel and common mechanism between spermiogenesis and oocyte maturation.
The authors speculate that the mutation likely affects chromatin remodeling after the major events of meiotic prophase I. So far, a relationship between sex-specific nuclear remodeling events in oocytes and spermatids has not been discovered, but BRWD1 may play a role. Bromodomain-containing proteins typically interact with and effect changes in chromatin during spermiogenesis, and Brwd1 is one of the few genes whose elimination disrupts gametogenesis in both sexes after the major events of meiotic prophase I are completed.
References
(Authors in bold are Jackson Laboratory scientists.)
JAX® NOTES. 2007. The Jackson Laboratory Reproductive Genomics program. JAX® NOTES 507:7-8.
Philipps DL, Wigglesworth K, Hartford SA, Sun F, Pattabiraman S, Schimenti K, Handel MA, Eppig JJ, Schimenti JC. 2008. The dual bromodomain and WD repeat-containing mouse protein BRWD1 is required for normal spermiogenesis and the oocyte—embryo transition.
Dev Biol 317:72-82.
