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Genetic Overlap in Kallmann Syndrome, Combined Pituitary Hormone Deficiency, and Septo-Optic Dysplasia

Lookup NU author(s): Dr Richard Quinton

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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).


Abstract

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)


Publication metadata

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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Funding

Funder referenceFunder name
U.K. Endocrine Research Fund
Academy of Finland
Pew Latin American Fellows Program in the Biomedical Sciences
Swiss National Foundation
HD15788Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health
P3-0343Slovene National Research Agency
R01HD056264Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health
T32 HD007396Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health
U54HD41859Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health

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