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Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 Are Identified in Individuals with Congenital Hypogonadotropic Hypogonadism

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 signal... Full description

Journal Title: American Journal of Human Genetics 2013-05-02, Vol.92 (5), p.725-743
Main Author: Miraoui, Hichem
Other Authors: Dwyer, Andrew A , Sykiotis, Gerasimos P , Plummer, Lacey , Chung, Wilson , Feng, Bihua , Beenken, Andrew , Clarke, Jeff , Pers, Tune H , Dworzynski, Piotr , Keefe, Kimberley , Niedziela, Marek , Raivio, Taneli , Crowley, William F , Seminara, Stephanie B , Quinton, Richard , Hughes, Virginia A , Kumanov, Philip , Young, Jacques , Yialamas, Maria A , Hall, Janet E , Van Vliet, Guy , Chanoine, Jean-Pierre , Rubenstein, John , Mohammadi, Moosa , Tsai, Pei-San , Sidis, Yisrael , Lage, Kasper , Pitteloud, Nelly
Format: Electronic Article Electronic Article
Language: English
Subjects:
Quelle: Alma/SFX Local Collection
Publisher: United States: Elsevier Inc
ID: ISSN: 0002-9297
Link: https://www.ncbi.nlm.nih.gov/pubmed/23643382
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title: Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 Are Identified in Individuals with Congenital Hypogonadotropic Hypogonadism
format: Article
creator:
  • Miraoui, Hichem
  • Dwyer, Andrew A
  • Sykiotis, Gerasimos P
  • Plummer, Lacey
  • Chung, Wilson
  • Feng, Bihua
  • Beenken, Andrew
  • Clarke, Jeff
  • Pers, Tune H
  • Dworzynski, Piotr
  • Keefe, Kimberley
  • Niedziela, Marek
  • Raivio, Taneli
  • Crowley, William F
  • Seminara, Stephanie B
  • Quinton, Richard
  • Hughes, Virginia A
  • Kumanov, Philip
  • Young, Jacques
  • Yialamas, Maria A
  • Hall, Janet E
  • Van Vliet, Guy
  • Chanoine, Jean-Pierre
  • Rubenstein, John
  • Mohammadi, Moosa
  • Tsai, Pei-San
  • Sidis, Yisrael
  • Lage, Kasper
  • Pitteloud, Nelly
subjects:
  • Algorithms
  • Animals
  • Article
  • Base Sequence
  • Bioinformatics
  • Computational Biology
  • Dual Specificity Phosphatase 6 - genetics
  • Female
  • Fibroblast Growth Factors - genetics
  • Gene expression
  • Gene mutations
  • Genes
  • Genetic aspects
  • Genetic Association Studies
  • Genetic disorders
  • Genetic Predisposition to Disease - genetics
  • Genetic research
  • Genetics
  • Genetics(clinical)
  • Humans
  • Hypogonadism
  • Hypogonadism - genetics
  • Immunohistochemistry
  • Inheritance Patterns - genetics
  • Intracellular Signaling Peptides and Proteins - genetics
  • Male
  • Membrane Proteins - genetics
  • Mice
  • Molecular Sequence Data
  • Mutation
  • Mutation - genetics
  • Nerve Tissue Proteins - genetics
  • Physiological aspects
  • Proteins
  • Receptors, Interleukin - genetics
  • Sequence Analysis, DNA
  • Sequence Homology
  • Surface Plasmon Resonance
ispartof: American Journal of Human Genetics, 2013-05-02, Vol.92 (5), p.725-743
description: 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.
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0002-9297
fulltext: fulltext
issn:
  • 0002-9297
  • 1537-6605
url: Link


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titleMutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 Are Identified in Individuals with Congenital Hypogonadotropic Hypogonadism
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creatorMiraoui, Hichem ; Dwyer, Andrew A ; Sykiotis, Gerasimos P ; Plummer, Lacey ; Chung, Wilson ; Feng, Bihua ; Beenken, Andrew ; Clarke, Jeff ; Pers, Tune H ; Dworzynski, Piotr ; Keefe, Kimberley ; Niedziela, Marek ; Raivio, Taneli ; Crowley, William F ; Seminara, Stephanie B ; Quinton, Richard ; Hughes, Virginia A ; Kumanov, Philip ; Young, Jacques ; Yialamas, Maria A ; Hall, Janet E ; Van Vliet, Guy ; Chanoine, Jean-Pierre ; Rubenstein, John ; Mohammadi, Moosa ; Tsai, Pei-San ; Sidis, Yisrael ; Lage, Kasper ; Pitteloud, Nelly
creatorcontribMiraoui, Hichem ; Dwyer, Andrew A ; Sykiotis, Gerasimos P ; Plummer, Lacey ; Chung, Wilson ; Feng, Bihua ; Beenken, Andrew ; Clarke, Jeff ; Pers, Tune H ; Dworzynski, Piotr ; Keefe, Kimberley ; Niedziela, Marek ; Raivio, Taneli ; Crowley, William F ; Seminara, Stephanie B ; Quinton, Richard ; Hughes, Virginia A ; Kumanov, Philip ; Young, Jacques ; Yialamas, Maria A ; Hall, Janet E ; Van Vliet, Guy ; Chanoine, Jean-Pierre ; Rubenstein, John ; Mohammadi, Moosa ; Tsai, Pei-San ; Sidis, Yisrael ; Lage, Kasper ; Pitteloud, Nelly
descriptionCongenital 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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1EISSN: 1537-6605
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languageeng
publisherUnited States: Elsevier Inc
subjectAlgorithms ; Animals ; Article ; Base Sequence ; Bioinformatics ; Computational Biology ; Dual Specificity Phosphatase 6 - genetics ; Female ; Fibroblast Growth Factors - genetics ; Gene expression ; Gene mutations ; Genes ; Genetic aspects ; Genetic Association Studies ; Genetic disorders ; Genetic Predisposition to Disease - genetics ; Genetic research ; Genetics ; Genetics(clinical) ; Humans ; Hypogonadism ; Hypogonadism - genetics ; Immunohistochemistry ; Inheritance Patterns - genetics ; Intracellular Signaling Peptides and Proteins - genetics ; Male ; Membrane Proteins - genetics ; Mice ; Molecular Sequence Data ; Mutation ; Mutation - genetics ; Nerve Tissue Proteins - genetics ; Physiological aspects ; Proteins ; Receptors, Interleukin - genetics ; Sequence Analysis, DNA ; Sequence Homology ; Surface Plasmon Resonance
ispartofAmerican Journal of Human Genetics, 2013-05-02, Vol.92 (5), p.725-743
rights
02013 The American Society of Human Genetics
1Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
2COPYRIGHT 2013 Elsevier B.V.
3Copyright Cell Press May 2, 2013
42013 The American Society of Human Genetics. Published by Elsevier Ltd. All right reserved. 2013 The American Society of Human Genetics
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1Dwyer, Andrew A
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7Clarke, Jeff
8Pers, Tune H
9Dworzynski, Piotr
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13Crowley, William F
14Seminara, Stephanie B
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16Hughes, Virginia A
17Kumanov, Philip
18Young, Jacques
19Yialamas, Maria A
20Hall, Janet E
21Van Vliet, Guy
22Chanoine, Jean-Pierre
23Rubenstein, John
24Mohammadi, Moosa
25Tsai, Pei-San
26Sidis, Yisrael
27Lage, Kasper
28Pitteloud, Nelly
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0Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 Are Identified in Individuals with Congenital Hypogonadotropic Hypogonadism
1American Journal of Human Genetics
addtitleAm J Hum Genet
descriptionCongenital 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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7Clarke, Jeff
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titleMutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 Are Identified in Individuals with Congenital Hypogonadotropic Hypogonadism
authorMiraoui, Hichem ; Dwyer, Andrew A ; Sykiotis, Gerasimos P ; Plummer, Lacey ; Chung, Wilson ; Feng, Bihua ; Beenken, Andrew ; Clarke, Jeff ; Pers, Tune H ; Dworzynski, Piotr ; Keefe, Kimberley ; Niedziela, Marek ; Raivio, Taneli ; Crowley, William F ; Seminara, Stephanie B ; Quinton, Richard ; Hughes, Virginia A ; Kumanov, Philip ; Young, Jacques ; Yialamas, Maria A ; Hall, Janet E ; Van Vliet, Guy ; Chanoine, Jean-Pierre ; Rubenstein, John ; Mohammadi, Moosa ; Tsai, Pei-San ; Sidis, Yisrael ; Lage, Kasper ; Pitteloud, Nelly
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31Nerve Tissue Proteins - genetics
32Physiological aspects
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34Receptors, Interleukin - genetics
35Sequence Analysis, DNA
36Sequence Homology
37Surface Plasmon Resonance
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1Dwyer, Andrew A
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atitleMutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 Are Identified in Individuals with Congenital Hypogonadotropic Hypogonadism
jtitleAmerican Journal of Human Genetics
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abstractCongenital 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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pubElsevier Inc
pmid23643382
doi10.1016/j.ajhg.2013.04.008
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