Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 Are Identified in Individuals with Congenital Hypogonadotropic Hypogonadism
Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 Are Identified in Individuals with Congenital Hypogonadotropic Hypogonadism
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DOI：
10.1016/j.ajhg.2013.04.008
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发表时间：
2013-05-02
影响因子：
9.8
通讯作者：
Pitteloud, Nelly
中科院分区：
文献类型：
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作者：
Miraoui, Hichem;Dwyer, Andrew A.;Pitteloud, Nelly
先天性低促性腺激素减退症(CHH)及其嗅觉缺失相关的形式(Kallmann综合征[KS])在遗传上是不同的。在这些疾病涉及的>；15基因中，FGF8和FGFR1的突变约占12%；值得注意的是，KAL1和HS6ST1也参与了FGFR1信号转导，并可在CHH中突变。因此，我们假设，编码更广泛范围的FGFR1途径调节器的基因突变可能有助于CHH的遗传学，使其成为因果突变或修饰突变。因此，我们的目标是(1)调查CHH个体是否在所谓的“FGF8共表达”组的成员中存在突变，以及(2)验证基于蛋白质-蛋白质相互作用组数据(基于相互作用组的从属关系评分[IBAS])的生物信息学算法识别高质量候选基因的能力。根据序列同源性、表达、结构和功能数据，在386名无关CHH个体和155名对照中选择了7个基因并进行了测序。除FGF18和SPRY2外，其余基因在CHH患者中均发生突变：FGF17(n=3)、IL17RD(n=8)、DUSP6(n=5)、SPRY4(n=14)和Flt3(n=3)。独立地，IBAS预测FGF17和IL17RD是整个蛋白质组中最重要的两个候选基因，这是基于对它们与已知在CHH中改变的蛋白质的蛋白质相互作用模式的统计测试。大多数FGF17和IL17RD突变在体外改变了蛋白质的功能。IL17RD突变仅在KS个体中发现，并且与听力损失密切相关(6/8个体)。成纤维细胞生长因子途径编码成分的基因突变与CHH遗传的复杂模式有关，并且主要是CHH背后的寡基因遗传结构的贡献者。
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 similar to 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.