Journal article
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-kappa B activation
European journal of endocrinology, v 166(4), pp 743-752
01 Apr 2012
PMID: 22214923
Featured in Collection : UN Sustainable Development Goals @ Drexel
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 IkB mutation suggests that the NF-kappa B 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-kappa B and related proteins. Functional studies on cultured skin fibroblasts revealed that NF-kappa B 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-kappa B 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-kappa B signaling, possibly due to PRKCA mRNA overexpression.
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Details
- Title
- 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-kappa B activation
- Creators
- D. Mul - Leiden University Medical CenterS. Wu - Xi An Jiao Tong Univ, Affiliated Hosp 1, Sch Med, Xian 710061, Shaanxi, Peoples R ChinaR. A. de Paus - Leiden Univ, Med Ctr, Dept Infect Dis, NL-2300 RC Leiden, NetherlandsW. Oostdijk - Leiden University Medical CenterA. C. Lankester - Leiden Univ, Med Ctr, Dept Pediat, NL-2300 RC Leiden, NetherlandsH. A. van Duyvenvoorde - Leiden Univ, Med Ctr, Dept Pediat, NL-2300 RC Leiden, NetherlandsC. A. L. Ruivenkamp - Leiden Univ, Med Ctr, Dept Clin Genet, NL-2300 RC Leiden, NetherlandsM. Losekoot - Leiden University Medical CenterM. J. D. van Tol - Leiden Univ, Med Ctr, Dept Pediat, NL-2300 RC Leiden, NetherlandsF. De Luca - Drexel Univ, Coll Med, St Christophers Hosp Children, Sect Endocrinol & Diabet, Philadelphia, PA 19104 USAE. van de Vosse - Leiden Univ, Med Ctr, Dept Infect Dis, NL-2300 RC Leiden, NetherlandsJ. M. Wit - Leiden Univ, Med Ctr, Dept Pediat, NL-2300 RC Leiden, NetherlandsFrancesco DeLuca - Pediatrics
- Publication Details
- European journal of endocrinology, v 166(4), pp 743-752
- Publisher
- Bioscientifica Ltd
- Number of pages
- 10
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pediatrics
- Web of Science ID
- WOS:000302343500022
- Scopus ID
- 2-s2.0-84859398147
- Other Identifier
- 991019168693304721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Endocrinology & Metabolism