👤 Matthew G Boden

Impaired function of gonadotropin-releasing hormone (GnRH) neurons can cause a phenotypic spectrum ranging from delayed puberty to isolated hypogonadotropic hypogonadism (IHH). We sought to identify a new genetic etiology for these conditions. Exome sequencing was performed in an extended family with autosomal dominant, markedly delayed puberty. The effects of the variant were studied in a GnRH neuronal cell line. Variants in the same gene were sought in a large cohort of individuals with IHH. We identified a rare missense variant (F900V) in DLG2 (which encodes PSD-93) that cosegregated with the delayed puberty. The variant decreased GnRH expression in vitro. PSD-93 is an anchoring protein of NMDA receptors, a type of glutamate receptor that has been implicated in the control of puberty in laboratory animals. The F900V variant impaired the interaction between PSD-93 and a known binding partner, Fyn, which phosphorylates NMDA receptors. Variants in DLG2 that also decreased GnRH expression were identified in three unrelated families with IHH. The findings indicate that variants in DLG2/PSD-93 cause autosomal dominant delayed puberty and may also contribute to IHH. The findings also suggest that the pathogenesis involves impaired NMDA receptor signaling and consequently decreased GnRH secretion. Show less

Diabetes mellitus (DM) is a prothrombotic and proinflammatory state. Hyperglycemia (HG) is encountered even in patients without DM. We have shown that combined HG and hyperinsulinemia (HI) in healthy non-diabetic subjects increased circulating tissue factor (TF) and thrombin generation. To understand the changes in platelet and monocyte pathways induced by combined HG and HI in healthy non-diabetic state, we performed whole genome expression profiling of leukocyte-depleted platelets and monocytes before and after 24 hours of combined HG (glucose ~200mg/dL) and HI by glucose infusion clamp in a healthy non-diabetic subject. We defined time-dependent differential mRNA expression (24 versus 0 hour fold change (FC) ≥ 2) common to platelets and monocytes. Ingenuity Pathways Analysis revealed alterations in canonical insulin receptor signaling and coagulation pathways. A preliminary group of 9 differentially expressed genes was selected for qRT-PCR confirmation. Platelet 24 hour sample was compared to the 0 hour sample plus 4 controls. Five transcripts in platelets and 6 in monocytes were confirmed. Platelet GSK3B and PTPN1 were upregulated, and STXBP4 was downregulated in insulin signaling, and F3 and TFPI were upregulated in coagulation pathways. Monocyte, PIK3C3, PTPN11 and TFPI were downregulated. Platelet GSKβ3 and PTPN11 protein and TF antigen in platelets and monocytes was increased. Even in non-diabetic state, HG+HI for 24 hours induces changes in platelets and monocytes. They suggest downregulation of insulin signaling and upregulation of TF. Further studies are needed to elucidate cellular alterations leading to the prothrombotic and proinflammatory state in DM. Show less