Convergent pathways underlying the Kallmann syndrome-linked genes Hs6st1 and Fgfr1

Kallmann syndrome (KS) is a congenital disorder characterized by idiopathic hypogonadotropic hypogonadism and olfactory dysfunction. KS is linked to variants in more than 24 genes, which are scattered across the human genome and show disparate biological functions. Although the genetic basis of KS is well studied, the mechanisms by which disruptions of these diverse genes cause KS are not fully understood. Overall design: Here we show that disruptions of KS-linked genes affect the same biological pathways, indicating a convergent mechanism underlying KS. We disrupted two KS-linked genes, Heparan sulfate 6-O-sulfotransferase 1 (Hs6st1) and fibroblast growth factor receptor 1 (Fgfr1), in mouse neuronal cells. We found that disruptions of Hs6st1 and Fgfr1 altered the same biological processes, the upregulation of extracellular pathways and the downregulation of nuclear pathways. Moreover, we found that Hs6st1 and Fgfr1 regulate gene transcription likely via the transcription factor Sox9/Sox10 and the chromatin regulator Chd7, which are also associated with KS.