Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism

H. Miraoui; A.A. Dwyer; V.A. Hughes; Y. Sidis; N. Pitteloud; G.P. Sykiotis; L. Plummer; B. Feng; K. Keefe; W.F. Crowley Jr.; S.B. Seminara; J.E. Hall; W. Chung; P.-S. Tsai; A. Beenken; M. Mohammadi; J. Clarke; J. Rubenstein; T.H. Pers; Piotr Dworzynski; Kasper Lage Hansen; M. Niedziela; T. Raivio; R. Quinton; P. Kumanov; Jette Feveile Young; M.A. Yialamas; G. Van Vliet; J.-P. Chanoine

doi:10.1016/j.ajhg.2013.04.008

Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism

H. Miraoui, A.A. Dwyer, V.A. Hughes, Y. Sidis, N. Pitteloud, G.P. Sykiotis, L. Plummer, B. Feng, K. Keefe, W.F. Crowley Jr., S.B. Seminara, J.E. Hall, W. Chung, P.-S. Tsai, A. Beenken, M. Mohammadi, J. Clarke, J. Rubenstein, T.H. Pers, Piotr DworzynskiKasper Lage Hansen, M. Niedziela, T. Raivio, R. Quinton, P. Kumanov, Jette Feveile Young, M.A. Yialamas, G. Van Vliet, J.-P. Chanoine

146 Citations (Scopus)

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.

Original language	English
Journal	American Journal of Human Genetics
Volume	92
Issue number	5
Pages (from-to)	725-743
Number of pages	19
ISSN	0002-9297
DOIs	https://doi.org/10.1016/j.ajhg.2013.04.008
Publication status	Published - 2 May 2013

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Miraoui, H., Dwyer, A. A., Hughes, V. A., Sidis, Y., Pitteloud, N., Sykiotis, G. P., Plummer, L., Feng, B., Keefe, K., Crowley Jr., W. F., Seminara, S. B., Hall, J. E., Chung, W., Tsai, P-S., Beenken, A., Mohammadi, M., Clarke, J., Rubenstein, J., Pers, T. H., ... Chanoine, J-P. (2013). Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism. American Journal of Human Genetics, 92(5), 725-743. https://doi.org/10.1016/j.ajhg.2013.04.008

Miraoui, H, Dwyer, AA, Hughes, VA, Sidis, Y, Pitteloud, N, Sykiotis, GP, Plummer, L, Feng, B, Keefe, K, Crowley Jr., WF, Seminara, SB, Hall, JE, Chung, W, Tsai, P-S, Beenken, A, Mohammadi, M, Clarke, J, Rubenstein, J, Pers, TH, Dworzynski, P, Hansen, KL, Niedziela, M, Raivio, T, Quinton, R, Kumanov, P, Young, JF, Yialamas, MA, Van Vliet, G & Chanoine, J-P 2013, 'Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism', American Journal of Human Genetics, vol. 92, no. 5, pp. 725-743. https://doi.org/10.1016/j.ajhg.2013.04.008

@article{46c5d3a23a114fa88ccd5d901f8ef14e,

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.",

author = "H. Miraoui and A.A. Dwyer and V.A. Hughes and Y. Sidis and N. Pitteloud and G.P. Sykiotis and L. Plummer and B. Feng and K. Keefe and {Crowley Jr.}, W.F. and S.B. Seminara and J.E. Hall and W. Chung and P.-S. Tsai and A. Beenken and M. Mohammadi and J. Clarke and J. Rubenstein and T.H. Pers and Piotr Dworzynski and Hansen, {Kasper Lage} and M. Niedziela and T. Raivio and R. Quinton and P. Kumanov and Young, {Jette Feveile} and M.A. Yialamas and {Van Vliet}, G. and J.-P. Chanoine",

year = "2013",

month = may,

day = "2",

doi = "10.1016/j.ajhg.2013.04.008",

language = "English",

volume = "92",

pages = "725--743",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "5",

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TY - JOUR

T1 - Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism

AU - Miraoui, H.

AU - Dwyer, A.A.

AU - Hughes, V.A.

AU - Sidis, Y.

AU - Pitteloud, N.

AU - Sykiotis, G.P.

AU - Plummer, L.

AU - Feng, B.

AU - Keefe, K.

AU - Crowley Jr., W.F.

AU - Seminara, S.B.

AU - Hall, J.E.

AU - Chung, W.

AU - Tsai, P.-S.

AU - Beenken, A.

AU - Mohammadi, M.

AU - Clarke, J.

AU - Rubenstein, J.

AU - Pers, T.H.

AU - Dworzynski, Piotr

AU - Hansen, Kasper Lage

AU - Niedziela, M.

AU - Raivio, T.

AU - Quinton, R.

AU - Kumanov, P.

AU - Young, Jette Feveile

AU - Yialamas, M.A.

AU - Van Vliet, G.

AU - Chanoine, J.-P.

PY - 2013/5/2

Y1 - 2013/5/2

N2 - 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.

AB - 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.

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U2 - 10.1016/j.ajhg.2013.04.008

DO - 10.1016/j.ajhg.2013.04.008

M3 - Journal article

C2 - 23643382

AN - SCOPUS:84877260745

SN - 0002-9297

VL - 92

SP - 725

EP - 743

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 5

ER -

Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism

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