title: Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism.
abstract: Congenital hypogonadotropic hypogonadism (CHH) and its anosmia-associated form (Kallmann syndrome [KS]) are genetically heterogeneous. Among the >15 genes implicated in these conditions, mutations in FGF8 and FGFR1 account for ~12% of cases; notably, KAL1 and HS6ST1 are also involved in FGFR1 signaling and can be mutated in CHH. We therefore hypothesized that mutations in genes encoding a broader range of modulators of the FGFR1 pathway might contribute to the genetics of CHH as causal or modifier mutations. Thus, we aimed to (1) investigate whether CHH individuals harbor mutations in members of the so-called "FGF8 synexpression" group and (2) validate the ability of a bioinformatics algorithm on the basis of protein-protein interactome data (interactome-based affiliation scoring [IBAS]) to identify high-quality candidate genes. On the basis of sequence homology, expression, and structural and functional data, seven genes were selected and sequenced in 386 unrelated CHH individuals and 155 controls. Except for FGF18 and SPRY2, all other genes were found to be mutated in CHH individuals: FGF17 (n = 3 individuals), IL17RD (n = 8), DUSP6 (n = 5), SPRY4 (n = 14), and FLRT3 (n = 3). Independently, IBAS predicted FGF17 and IL17RD as the two top candidates in the entire proteome on the basis of a statistical test of their protein-protein interaction patterns to proteins known to be altered in CHH. Most of the FGF17 and IL17RD mutations altered protein function in vitro. IL17RD mutations were found only in KS individuals and were strongly linked to hearing loss (6/8 individuals). Mutations in genes encoding components of the FGF pathway are associated with complex modes of CHH inheritance and act primarily as contributors to an oligogenic genetic architecture underlying CHH.
authors: Faculty of Biology and Medicine, University of Lausanne in collaboration with Service of Endocrinology, Diabetology, and Metabolism, Centre Hospitalier Universitaire Vaudois, Rue du Bugnon 7, Lausanne CH-1005, Switzerland.
authors: Hichem
authors: H
authors: Miraoui
authors: Andrew A
authors: AA
authors: Dwyer
authors: Gerasimos P
authors: GP
authors: Sykiotis
authors: Lacey
authors: L
authors: Plummer
authors: Wilson
authors: W
authors: Chung
authors: Bihua
authors: B
authors: Feng
authors: Andrew
authors: A
authors: Beenken
authors: Jeff
authors: J
authors: Clarke
authors: Tune H
authors: TH
authors: Pers
authors: Piotr
authors: P
authors: Dworzynski
authors: Kimberley
authors: K
authors: Keefe
authors: Marek
authors: M
authors: Niedziela
authors: Taneli
authors: T
authors: Raivio
authors: William F
authors: WF
authors: Crowley
authors: Stephanie B
authors: SB
authors: Seminara
authors: Richard
authors: R
authors: Quinton
authors: Virginia A
authors: VA
authors: Hughes
authors: Philip
authors: P
authors: Kumanov
authors: Jacques
authors: J
authors: Young
authors: Maria A
authors: MA
authors: Yialamas
authors: Janet E
authors: JE
authors: Hall
authors: Guy
authors: G
authors: Van Vliet
authors: Jean-Pierre
authors: JP
authors: Chanoine
authors: John
authors: J
authors: Rubenstein
authors: Moosa
authors: M
authors: Mohammadi
authors: Pei-San
authors: PS
authors: Tsai
authors: Yisrael
authors: Y
authors: Sidis
authors: Kasper
authors: K
authors: Lage
authors: Nelly
authors: N
authors: Pitteloud
mesh_terms: D000465:Algorithms; D000818:Animals; D001483:Base Sequence; D019295:Computational Biology; D054642:Dual Specificity Phosphatase 6 / Q000235:genetics*; D005260:Female; D005346:Fibroblast Growth Factors / Q000235:genetics*; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007006:Hypogonadism / Q000235:genetics*; D007150:Immunohistochemistry; D040582:Inheritance Patterns / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics*; D018123:Receptors, Interleukin / Q000235:genetics*; D017422:Sequence Analysis, DNA; D017385:Sequence Homology; D020349:Surface Plasmon Resonance
chemical_list: C484724:FGF17 protein, human; C404492:FLRT3 protein, human; C477526:IL17RD protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D018123:Receptors, Interleukin; C499038:SPRY4 protein, human; D005346:Fibroblast Growth Factors; C517035:DUSP6 protein, human; D054642:Dual Specificity Phosphatase 6
references: J Clin Endocrinol Metab. 2009 Nov;94(11):4380-90
references: 19820032
references: Proc Natl Acad Sci U S A. 2009 Jul 14;106(28):11703-8
references: 19567835
references: Nat Methods. 2010 Aug;7(8):575-6
references: 20676075
references: Hippocampus. 2012 Mar;22(3):434-41
references: 21240919
references: Neuron. 2002 Aug 15;35(4):671-80
references: 12194867
references: Nat Methods. 2010 Apr;7(4):248-9
references: 20354512
references: Cell. 1991 Oct 18;67(2):423-35
references: 1913827
references: Nat Protoc. 2009;4(7):1073-81
references: 19561590
references: Proc Natl Acad Sci U S A. 2011 Jul 12;108(28):11524-9
references: 21700882
references: Methods. 2001 Apr;23(4):335-8
references: 11316434
references: Nat Rev Endocrinol. 2009 Oct;5(10):569-76
references: 19707180
references: Development. 2000 May;127(9):1833-43
references: 10751172
references: Fertil Steril. 2011 Dec;96(6):1424-1430.e6
references: 22035731
references: Dev Cell. 2005 Apr;8(4):565-74
references: 15809038
references: J Clin Endocrinol Metab. 2011 Nov;96(11):E1771-81
references: 21880801
references: J Comp Neurol. 2008 Oct 1;510(4):422-39
references: 18666124
references: Endocrinology. 2008 Oct;149(10):4997-5003
references: 18566132
references: Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1757-62
references: 12574514
references: Proc Natl Acad Sci U S A. 2007 May 1;104(18):7652-7
references: 17442747
references: J Clin Endocrinol Metab. 2011 Mar;96(3):E566-76
references: 21209029
references: Mech Dev. 2002 May;113(2):193-6
references: 11960712
references: J Biol Chem. 1995 Jul 14;270(28):16483-6
references: 7622446
references: Biochem Biophys Res Commun. 2007 Jan 26;352(4):896-902
references: 17156747
references: Mech Dev. 2002 May;113(2):163-8
references: 11960706
references: J Clin Endocrinol Metab. 2002 Sep;87(9):4128-36
references: 12213860
references: Mol Cell Neurosci. 2004 Oct;27(2):202-14
references: 15485775
references: Brain Res Brain Res Rev. 2005 Sep;49(2):158-66
references: 16111546
references: Clin Endocrinol (Oxf). 2001 Aug;55(2):163-74
references: 11531922
references: Genes Dev. 2005 Mar 1;19(5):603-13
references: 15741321
references: J Biol Chem. 2003 Apr 18;278(16):14087-91
references: 12604616
references: Genes Dev. 2002 Apr 1;16(7):870-9
references: 11937494
references: Genes Dev. 2002 Apr 1;16(7):859-69
references: 11937493
references: Dev Cell. 2004 Jul;7(1):33-44
references: 15239952
references: Proc Natl Acad Sci U S A. 2008 Dec 30;105(52):20870-5
references: 19104045
references: Am J Med Genet. 1983 Jul;15(3):417-35
references: 6881209
references: Mech Dev. 1999 Mar;81(1-2):213-6
references: 10330503
references: Nat Genet. 1998 Feb;18(2):136-41
references: 9462741
references: Development. 2010 Aug 1;137(15):2471-81
references: 20573694
references: J Clin Endocrinol Metab. 1996 Dec;81(12):4388-95
references: 8954047
references: Nature. 1991 Oct 10;353(6344):529-36
references: 1922361
references: Mol Endocrinol. 2005 Jan;19(1):225-36
references: 15459253
references: Nat Genet. 2009 Mar;41(3):354-358
references: 19079066
references: Development. 2005 Dec;132(23):5211-23
references: 16267092
references: J Clin Invest. 2007 Feb;117(2):457-63
references: 17235395
references: Nat Genet. 2000 Dec;26(4):460-3
references: 11101846
references: Nat Cell Biol. 2004 Jan;6(1):38-44
references: 14688794
references: Proc Natl Acad Sci U S A. 2010 Aug 24;107(34):15140-4
references: 20696889
references: J Neurosci. 2007 Apr 18;27(16):4273-82
references: 17442811
references: Mol Syst Biol. 2010 Jun 22;6:381
references: 20571530
references: J Neurosci. 2004 Nov 17;24(46):10384-92
references: 15548653
references: Dev Biol. 2005 Nov 15;287(2):390-402
references: 16216232
references: PLoS One. 2011;6(10):e25614
references: 22031817
references: Development. 2005 Sep;132(17):3859-71
references: 16049111
references: J Comput Biol. 1997 Fall;4(3):311-23
references: 9278062
references: Genes Dev. 2006 Jan 15;20(2):185-98
references: 16384934
references: Mol Cell Endocrinol. 2011 Oct 22;346(1-2):37-43
references: 21664428
references: PLoS One. 2012;7(2):e32087
references: 22384148
references: Nat Biotechnol. 2007 Mar;25(3):309-16
references: 17344885
references: EMBO J. 2011 Jun 14;30(14):2920-33
references: 21673655
references: Mech Dev. 2001 Apr;102(1-2):81-94
references: 11287183
references: J Clin Invest. 2008 Aug;118(8):2822-31
references: 18596921
references: Dev Biol. 2008 Jun 1;318(1):184-93
references: 18448090
references: Nat Cell Biol. 2002 Feb;4(2):165-9
references: 11802164
references: Dev Cell. 2005 Apr;8(4):553-64
references: 15809037
references: Mech Dev. 2001 Feb;100(2):313-6
references: 11165488
references: Biol Reprod. 2012 Apr 19;86(4):119
references: 22278983
references: Development. 2007 Jan;134(1):167-76
references: 17164422
references: Nat Genet. 2003 Apr;33(4):463-5
references: 12627230
references: Proteins. 2004 Dec 1;57(4):811-9
references: 15390262
references: Sci Transl Med. 2010 May 19;2(32):32rv2
references: 20484732
references: Nature. 2002 May 2;417(6884):35-6
references: 11986655
references: Biochem Cell Biol. 2000;78(5):577-84
references: 11103948
references: J Clin Endocrinol Metab. 2010 Jun;95(6):2857-67
references: 20332248
references: Cell Calcium. 2013 Mar;53(3):224-30
references: 23337371
references: Genesis. 2005 Mar;41(3):110-5
references: 15729686
references: Nat Cell Biol. 2002 Feb;4(2):170-4
references: 11802165
references: Eur J Biochem. 2002 May;269(10):2546-56
references: 12027893