Insulin resistance and exaggerated insulin sensitivity triggered by single-gene mutations in the insulin signaling pathway.

Whereas the genetic basis of insulin sensitivity is determined by variation in multiple genes, mutations of single genes can give rise to profound changes in such sensitivity. Mutations of the insulin receptor gene (INSR)-which trigger type A insulin resistance, Rabson-Mendenhall, or Donohue syndromes-and those of the gene for the p85α regulatory subunit of phosphoinositide 3-kinase (PIK3R1), which give rise to SHORT syndrome, are the most common and second most common causes, respectively, of single-gene insulin resistance. Loss-of-function mutations of the genes for the protein kinase Akt2 (AKT2) or for TBC1 domain family member 4 (TBC1D4) have been identified in families with severe insulin resistance. Gain-of-function mutations of the gene for protein tyrosine phosphatase nonreceptor type 11 (PTPN11), which negatively regulates insulin receptor signaling, give rise to Noonan syndrome, and some individuals with this syndrome manifest insulin resistance. Gain-of-function mutations of the gene for the p110α catalytic subunit of phosphoinositide 3-kinase (PIK3CA) have been identified in individuals with segmental overgrowth or megalencephaly, some of whom also manifest spontaneous hypoglycemia. A gain-of-function mutation of AKT2 was also found in individuals with recurrent hypoglycemia. Loss-of-function mutations of the gene for phosphatase and tensin homolog (PTEN), another negative regulator of insulin signaling, give rise to Cowden syndrome in association with exaggerated metabolic actions of insulin. Clinical manifestations of individuals with such mutations of genes related to insulin signaling thus provide insight into the essential function of such genes in the human body.

Regulation of mitosis-meiosis transition by the ubiquitin ligase ß-TrCP in male germ cells.

The mitosis-meiosis transition is essential for spermatogenesis. Specific and timely downregulation of the transcription factor DMRT1, and consequent induction of Stra8 expression, is required for this process in mammals, but the molecular mechanism has remained unclear. Here, we show that ß-TrCP, the substrate recognition component of an E3 ubiquitin ligase complex, targets DMRT1 for degradation and thereby controls the mitosis-meiosis transition in mouse male germ cells. Conditional inactivation of ß-TrCP2 in male germ cells of ß-TrCP1 knockout mice resulted in sterility due to a lack of mature sperm. The ß-TrCP-deficient male germ cells did not enter meiosis, but instead underwent apoptosis. The induction of Stra8 expression was also attenuated in association with the accumulation of DMRT1 at the Stra8 promoter in ß-TrCP-deficient testes. DMRT1 contains a consensus ß-TrCP degron sequence that was found to bind ß-TrCP. Overexpression of ß-TrCP induced the ubiquitylation and degradation of DMRT1. Heterozygous deletion of Dmrt1 in ß-TrCP-deficient spermatogonia increased meiotic cells with a concomitant reduction of apoptosis. Collectively, our data indicate that ß-TrCP regulates the transition from mitosis to meiosis in male germ cells by targeting DMRT1 for degradation.