• PMID: 23643382
• Gene Name: DUSP6
• Condition: Congenital hypogonadotropic hypogonadism (CHH), Kallmann syndrome (KS)
• Association: 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
• Population size: 541
• Population details: 541 (386 unrelated CHH individuals, 155 controls)
• Sex: Male
• Infertility type: Male infertility
• Associated genes: FGF17, IL17RD, DUSP6, SPRY4, and FLRT3
• Other associated phenotypes: Congenital hypogonadotropic hypogonadism (CHH), Kallmann syndrome (KS)

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

Miraoui H, Dwyer AA, Sykiotis GP, Plummer L, Chung W, Feng B, Beenken A, Clarke J, Pers TH, Dworzynski P, Keefe K, Niedziela M, Raivio T, Crowley WF Jr, Seminara SB, Quinton R, Hughes VA, Kumanov P, Young J, Yialamas MA, Hall JE, Van Vliet G, Chanoine JP, Rubenstein J, Mohammadi M, Tsai PS, Sidis Y, Lage K, Pitteloud N.

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. CI - Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved. FAU - Miraoui, Hichem AU - Miraoui H AD - 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. FAU - Dwyer, Andrew A AU - Dwyer AA FAU - Sykiotis, Gerasimos P AU - Sykiotis GP FAU - Plummer, Lacey AU - Plummer L FAU - Chung, Wilson AU - Chung W FAU - Feng, Bihua AU - Feng B FAU - Beenken, Andrew AU - Beenken A FAU - Clarke, Jeff AU - Clarke J FAU - Pers, Tune H AU - Pers TH FAU - Dworzynski, Piotr AU - Dworzynski P FAU - Keefe, Kimberley AU - Keefe K FAU - Niedziela, Marek AU - Niedziela M FAU - Raivio, Taneli AU - Raivio T FAU - Crowley, William F Jr AU - Crowley WF Jr FAU - Seminara, Stephanie B AU - Seminara SB FAU - Quinton, Richard AU - Quinton R FAU - Hughes, Virginia A AU - Hughes VA FAU - Kumanov, Philip AU - Kumanov P FAU - Young, Jacques AU - Young J FAU - Yialamas, Maria A AU - Yialamas MA FAU - Hall, Janet E AU - Hall JE FAU - Van Vliet, Guy AU - Van Vliet G FAU - Chanoine, Jean-Pierre AU - Chanoine JP FAU - Rubenstein, John AU - Rubenstein J FAU - Mohammadi, Moosa AU - Mohammadi M FAU - Tsai, Pei-San AU - Tsai PS FAU - Sidis, Yisrael AU - Sidis Y FAU - Lage, Kasper AU - Lage K