A mosaic de novo duplication of 17q21-25 is associated with GH insensitivity, disturbed in vitro CD28-mediated signaling, and decreased STAT5B, PI3K, and NF-κB activation

Abstract

Objective: The established causes of GH insensitivity include defects of the GH receptor and STAT5B. The latter condition is also characterized by severe immunodeficiency. A recent case with short stature, GH resistance, and immunodeficiency due to an IκB mutation suggests that the NF-κB pathway may interact with STAT5B signaling. Design: Here, we present a case of a short child with several congenital anomalies as well as GH insensitivity and mild immunodeficiency associated with a mosaic de novo duplication of chromosome 17q21-25, suggesting that overexpression of one of the duplicated genes may be implicated in GH resistance. Methods and results: In vitro studies on blood lymphocytes showed disturbed signaling of the CD28 pathway, involving NF-κB and related proteins. Functional studies on cultured skin fibroblasts revealed that NF-κB activation, PI3K activity, and STAT5 phosphorylation in response to GH were suppressed, while the sensitivity to GH in terms of MAPK phosphorylation was increased. An in silico analysis of the duplicated genes showed that MAP3K3 and PRKCA are associated with the NF-κB pathway. Baseline MAP3K3 expression in T-cell blasts (TCBs) was normal, but PRKCA expression in TCBs and fibroblasts was significantly higher than that in control cells. Conclusions: We conclude that the 17q21-25 duplication is associated with GH insensitivity and disturbed STAT5B, PI3K, and NF-κB signaling, possibly due to PRKCA mRNA overexpression. © 2012 European Society of Endocrinology.