Genetic overlap in Kallmann syndrome, combined pituitary hormone deficiency, and septo-optic dysplasia.
BACKGROUND
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.


METHODS
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.
Children's Hospital, Helsinki University Central Hospital, Institute of Biomedicine/Physiology, University of Helsinki 00290 Helsinki, Finland.
Taneli
T
Raivio
Magdalena
M
Avbelj
Mark J
MJ
McCabe
Christopher J
CJ
Romero
Andrew A
AA
Dwyer
Johanna
J
Tommiska
Gerasimos P
GP
Sykiotis
Louise C
LC
Gregory
Daniel
D
Diaczok
Vaitsa
V
Tziaferi
Mariet W
MW
Elting
Raja
R
Padidela
Lacey
L
Plummer
Cecilia
C
Martin
Bihua
B
Feng
Chengkang
C
Zhang
Qun-Yong
QY
Zhou
Huaibin
H
Chen
Moosa
M
Mohammadi
Richard
R
Quinton
Yisrael
Y
Sidis
Sally
S
Radovick
Mehul T
MT
Dattani
Nelly
N
Pitteloud
D000818:Animals; D005260:Female; D051524:Fibroblast Growth Factor 8 / Q000235:genetics* / Q000378:metabolism; D056726:Genetic Association Studies; D006579:Heterozygote; D006801:Humans; D007018:Hypopituitarism / Q000235:genetics* / Q000378:metabolism; D017436:Kallmann Syndrome / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010904:Pituitary Gland, Posterior / Q000378:metabolism / Q000473:pathology; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D018000:Receptors, Peptide / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D025962:Septo-Optic Dysplasia / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D006113:United Kingdom; D014481:United States
C496456:FGF8 protein, human; D009419:Nerve Tissue Proteins; C470838:PROKR2 protein, human; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; D011993:Recombinant Fusion Proteins; D051524:Fibroblast Growth Factor 8; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1