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.
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.
Authors: Frédéric Brioude; Jérôme Bouligand; Séverine Trabado; Bruno Francou; Sylvie Salenave; Peter Kamenicky; Sylvie Brailly-Tabard; Philippe Chanson; Anne Guiochon-Mantel; Jacques Young Journal: Eur J Endocrinol Date: 2010-03-05 Impact factor: 6.664
Authors: Nelly Pitteloud; Richard Quinton; Simon Pearce; Taneli Raivio; James Acierno; Andrew Dwyer; Lacey Plummer; Virginia Hughes; Stephanie Seminara; Yu-Zhu Cheng; Wei-Ping Li; Gavin Maccoll; Anna V Eliseenkova; Shaun K Olsen; Omar A Ibrahimi; Frances J Hayes; Paul Boepple; Janet E Hall; Pierre Bouloux; Moosa Mohammadi; William Crowley Journal: J Clin Invest Date: 2007-01-18 Impact factor: 14.808
Authors: Hyung-Goo Kim; Ingo Kurth; Fei Lan; Irene Meliciani; Wolfgang Wenzel; Soo Hyun Eom; Gil Bu Kang; Georg Rosenberger; Mustafa Tekin; Metin Ozata; David P Bick; Richard J Sherins; Steven L Walker; Yang Shi; James F Gusella; Lawrence C Layman Journal: Am J Hum Genet Date: 2008-10-02 Impact factor: 11.025
Authors: Michelle L Brinkmeier; Shannon W Davis; Piero Carninci; James W MacDonald; Jun Kawai; Debashis Ghosh; Yoshihide Hayashizaki; Robert H Lyons; Sally A Camper Journal: Genomics Date: 2009-02-11 Impact factor: 5.736
Authors: Daniel Kelberman; Karine Rizzoti; Robin Lovell-Badge; Iain C A F Robinson; Mehul T Dattani Journal: Endocr Rev Date: 2009-10-16 Impact factor: 19.871
Authors: Zaid Mohsen; Hosung Sim; David Garcia-Galiano; Xingfa Han; Nicole Bellefontaine; Thomas L Saunders; Carol F Elias Journal: Brain Struct Funct Date: 2017-06-14 Impact factor: 3.270
Authors: M Severino; A E M Allegri; A Pistorio; B Roviglione; N Di Iorgi; M Maghnie; A Rossi Journal: AJNR Am J Neuroradiol Date: 2014-04-24 Impact factor: 3.825
Authors: Kathryn B Garber; Lisa M Vincent; John J Alexander; Lora J H Bean; Sherri Bale; Madhuri Hegde Journal: Am J Hum Genet Date: 2016-10-27 Impact factor: 11.025
Authors: Qing Fang; Akima S George; Michelle L Brinkmeier; Amanda H Mortensen; Peter Gergics; Leonard Y M Cheung; Alexandre Z Daly; Adnan Ajmal; María Ines Pérez Millán; A Bilge Ozel; Jacob O Kitzman; Ryan E Mills; Jun Z Li; Sally A Camper Journal: Endocr Rev Date: 2016-11-09 Impact factor: 19.871
Authors: Brent S Abel; Natalie D Shaw; Jenifer M Brown; Judith M Adams; Teresa Alati; Kathryn A Martin; Nelly Pitteloud; Stephanie B Seminara; Lacey Plummer; Duarte Pignatelli; William F Crowley; Corrine K Welt; Janet E Hall Journal: J Clin Endocrinol Metab Date: 2013-01-22 Impact factor: 5.958