During mammalian gonadal development, nuclear import/export of the transcription factor SOX9 is a critical step of the Sry‐initiated testis‐determining cascade. In this study, we identify a molecular mechanism contributing to the SOX9 nuclear translocation in NT2/D1 cells, which is mediated by the prostaglandin D2 (PGD2) signalling pathway via stimulation of its adenylcyclase‐coupled DP1 receptor. We find that activation of cAMP‐dependent protein kinase A (PKA) induces phosphorylation of SOX9 on its two S64 and S181 PKA sites, and its nuclear localization by enhancing SOX9 binding to the nucleocytoplasmic transport protein importin β. Moreover, in embryonic gonads, we detect a male‐specific prostaglandin D synthase expression and an active PGD2 signal at the time and place of SOX9 expression. We thus propose a new step in the sex‐determining cascade where PGD2 acts as an autocrine factor inducing SOX9 nuclear translocation and subsequent Sertoli cell differentiation.

Objective Familial Mediterranean fever (FMF) is a genetically recessive inflammatory disease caused by mutations in the MEFV gene. Most patients of non-Ashkenazi Jewish ancestry or those who are homozygous for M694V manifest a severe disease course, but some express a mild form of the disease. We therefore searched for other genes which could possibly be implicated in the disease phenotype. We tested MICA (major histocompatibility complex class I chain–related gene A) because it has been associated with a number of other inflammatory disorders. Methods One hundred fifty FMF probands and their family members were evaluated. The MEFV gene was screened by a combination of denaturing gradient-gel electrophoresis, restriction fragment length polymorphism, and amplification refractory mutation system. The MICA transmembrane polymorphism in exon 5 was analyzed after biotin-labeled polymerase chain reaction products were loaded onto sequencing gels and subjected to autoradiography. Results The contribution of MICA to the FMF phenotype was confirmed after adjustment for the patient's ancestry and for the MEFV genotype. MEFV was individually the most important prognostic factor for the disease. However, the impact of M694V homozygosity on the age at disease onset (OR 2.3) was aggravated if patients also inherited MICA-A9 (OR 6.3). In contrast, the frequency of attacks was found to be dramatically reduced (OR 0.16) in patients with MICA-A4. Conclusion We have identified the first FMF modifier locus, MICA. FMF is the first model of a Mendelian disease associated with MICA. These results clarify, at least partly, the inconsistent phenotype–MEFV correlation in FMF.