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Lookup NU author(s): Dr Richard Quinton
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).
Context: Kallmann syndrome (KS), combined pituitary hormone deficiency (CPHD), and septo-optic dysplasia (SOD) all result from development defects of the anterior midline in the human forebrain. Objective: The objective of the study was to investigate whether KS, CPHD, and SOD have shared genetic origins. Design and Participants: A total of 103 patients with either CPHD (n = 35) or SOD (n = 68) were investigated for mutations in genes implicated in the etiology of KS(FGFR1, FGF8, PROKR2, PROK2, and KAL1). Consequences of identified FGFR1, FGF8, and PROKR2 mutations were investigated in vitro. Results: Three patients with SOD had heterozygous mutations in FGFR1; these were either shown to alter receptor signaling (p.S450F, p.P483S) or predicted to affect splicing (c.336C > T, p.T112T). One patient had a synonymous change in FGF8 (c.216G > A, p.T72T) that was shown to affect splicing and ligand signaling activity. Four patients with CPHD/SOD were found to harbor heterozygous rare loss-of-function variants in PROKR2 (p.R85G, p.R85H, p.R268C). Conclusions: Mutations in FGFR1/FGF8/PROKR2 contributed to 7.8% of our patients with CPHD/SOD. These data suggest a significant genetic overlap between conditions affecting the development of anterior midline in the human forebrain. (J Clin Endocrinol Metab 97: E694-E699, 2012)
Author(s): Raivio T, Avbelj M, McCabe MJ, Romero CJ, Dwyer AA, Tommiska J, Sykiotis GP, Gregory LC, Diaczok D, Tziaferi V, Elting MW, Padidela R, Plummer L, Martin C, Feng BH, Zhang CK, Zhou QY, Chen HB, Mohammadi M, Quinton R, Sidis Y, Radovick S, Dattani MT, Pitteloud N
Publication type: Article
Publication status: Published
Journal: Journal of Clinical Endocrinology and Metabolism
Year: 2012
Volume: 97
Issue: 4
Pages: E694-E699
Online publication date: 08/02/2012
Acceptance date: 09/01/2012
Date deposited: 13/08/2014
ISSN (print): 0021-972X
ISSN (electronic): 1945-7197
Publisher: The Endocrine Society
URL: http://dx.doi.org/10.1210/jc.2011-2938
DOI: 10.1210/jc.2011-2938
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