TY - JOUR
T1 - Genetic overlap in Kallmann syndrome, combined pituitary hormone deficiency, and septo-optic dysplasia
AU - Raivio, Taneli
AU - Avbelj, Magdalena
AU - McCabe, Mark J.
AU - Romero, Christopher J.
AU - Dwyer, Andrew A.
AU - Tommiska, Johanna
AU - Sykiotis, Gerasimos P.
AU - Gregory, Louise C.
AU - Diaczok, Daniel
AU - Tziaferi, Vaitsa
AU - Elting, Mariet W.
AU - Padidela, Raja
AU - Plummer, Lacey
AU - Martin, Cecilia
AU - Feng, Bihua
AU - Zhang, Chengkang
AU - Zhou, Qun Yong
AU - Chen, Huaibin
AU - Mohammadi, Moosa
AU - Quinton, Richard
AU - Sidis, Yisrael
AU - Radovick, Sally
AU - Dattani, Mehul T.
AU - Pitteloud, Nelly
PY - 2012/4
Y1 - 2012/4
N2 - 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 gene simplicated 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.
AB - 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 gene simplicated 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.
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U2 - 10.1210/jc.2011-2938
DO - 10.1210/jc.2011-2938
M3 - Article
C2 - 22319038
AN - SCOPUS:84859524036
SN - 0021-972X
VL - 97
SP - E694-E699
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 4
ER -