Two novel mutations in the gonadotropin-releasing hormone receptor gene in Brazilian patients with hypogonadotropic hypogonadism and normal olfaction.
Two novel mutations in the gonadotropin-releasing hormone receptor gene in Brazilian patients with hypogonadotropic hypogonadism and normal olfaction.
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DOI：
10.1210/jcem.86.6.7551
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发表时间：
2001-06
期刊：
影响因子：
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通讯作者：
E. Costa;G. Bédécarrats;B. Mendonca;I. Arnhold;U. Kaiser;A. Latronico
中科院分区：
文献类型：
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作者：
E. Costa;G. Bédécarrats;B. Mendonca;I. Arnhold;U. Kaiser;A. Latronico
GnRH受体基因的几个点突变已被描述为一种常染色体隐性形式的先天性孤立性低促性腺激素减退症(HH)。我们调查了来自14个不同家庭的17名巴西患者(10名男性和7名女性)，他们患有HH，嗅觉正常。HH的诊断是基于17岁以后没有或不完全的性发育，伴随着男性的黄体生成素水平低或正常，男性的睾酮水平低，女性的雌二醇水平低。所有患者在嗅觉特异性测试中都表现出正常的嗅觉。用聚合酶链式反应扩增GnRH受体基因编码区，并直接测序。在1例女性完全性HH患者中，发现了一种新的错义突变Arg(139)His，位于GnRH受体第三跨膜和第二细胞内环交界处的保守DRS基序上，处于纯合子状态。Arg(139)His突变完全消除了可检测到的GnRH结合活性，并阻止了GnRH在体外诱导的肌醇磷酸积累的刺激。在另一个家系中，在4个部分HH的同胞(2男2女)中发现了一个新的复合杂合性突变(ASN(10)Lys和Gln(106)Arg)。位于第一细胞外环的Gln(106)Arg突变已被描述，体外分析表明突变的受体能够与GnRH结合，但亲和力降低。受体胞外氨基末端区域的ASN(10)Lys突变也降低了体外对GnRH的亲和力。在这个家族中，我们还发现了先前描述的第二细胞内环第151位氨基酸的沉默多态，该多态与GnRH受体的两个失活突变分离。在两名无GnRH受体功能突变的散发性HH患者中也发现了该基因多态。在其余病例中未发现突变。在我们的患者中，发现基因和表型之间有很好的相关性。这名妇女是完全失活的Arg(139)His突变的纯合子，患有完全性HH，血清基础促黄体生成素和卵泡刺激素水平检测不到，对促性腺激素释放激素刺激没有反应。此外，受影响的患者是ASN(10)Lys/Gln(106)Arg突变的复合杂合子，具有对GnRH刺激敏感的部分HH和低基础血清LH水平。在GnRH受体基因突变的HH患者和无GnRH受体突变的HH患者之间，没有发现临床和激素方面的差异，表明这些数据不有助于识别GnRH受体突变的HH患者。综上所述，我们报道了一例女性完全性HH患者GnRH受体保守的DRS基序中的第一个自然发生的突变，以及一个新的复合杂合性突变(ASN(10)Lys和Gln(106)Arg)，增加了GnRH受体失活突变的谱系。
Several point mutations in the GnRH receptor gene have been described in an autosomal recessive form of congenital isolated hypogonadotropic hypogonadism (HH). We investigated 17 Brazilian patients (10 males and 7 females) from 14 different families, with HH and normal olfaction. The diagnosis of HH was based on absent or incomplete sexual development after 17 yr of age associated with low or normal levels of LH in both sexes and low levels of testosterone in males and of estradiol in females. All patients presented with a normal sense of smell in an olfactory specific test. The coding region of the GnRH receptor gene was amplified by PCR and directly sequenced. A novel missense mutation, Arg(139)His, located in the conserved DRS motif at the junction of the third transmembrane and the second intracellular loop of the GnRH receptor was identified in the homozygous state in one female with complete HH. The Arg(139)His mutation completely eliminated detectable GnRH-binding activity and prevented GnRH-induced stimulation of inositol phosphate accumulation in vitro. In another family, a new compound heterozygous mutation (Asn(10)Lys and Gln(106)Arg) was identified in four siblings (two males and two females) with partial HH. The Gln(106)Arg mutation, located in the first extracellular loop, has been previously described, and in vitro analysis indicated that the mutant receptor was able to bind GnRH, but with a reduced affinity. The Asn(10)Lys mutation in the extracellular amino-terminal domain of the receptor also reduced the affinity for GnRH in vitro. In this family we also identified a previously described silent polymorphism at amino acid residue 151 in the second intracellular loop that segregated with the two inactivating mutations of the GnRH receptor. This polymorphism was also found in two unrelated patients with sporadic HH without GnRH receptor loss of function mutations. No mutations were identified in the remaining cases. A good correlation between genotype and phenotype was found in our patients. The woman, who is homozygous for the completely inactivating Arg(139)His mutation, has complete HH with undetectable serum basal LH and FSH levels that failed to respond to GnRH stimulation. In addition, the affected patients who are compound heterozygotes for the Asn(10)Lys/Gln(106)Arg mutations, have partial HH with low serum basal LH levels that were responsive to GnRH stimulation. No clinical or hormonal differences were found between HH patients with and without mutations in the GnRH receptor gene, indicating that these data do not contribute to the identification of HH patients with GnRH receptor mutations. In conclusion, we report the first naturally occurring mutation within the conserved DRS motif of the GnRH receptor in a female with complete HH and a novel compound heterozygous mutation (Asn(10)Lys and Gln(106)Arg) in a family with partial HH, increasing the repertoire of the inactivating mutations of the GnRH receptor.