Fathi Aws K, Hu Sicui, Fu Xi, Huang Shan, Liang Yan, Ning Qin, Luo Xiaoping
Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
J Pediatr Endocrinol Metab. 2012;25(7-8):659-68. doi: 10.1515/jpem-2012-0087.
Human mutations in the gonadotropin-releasing hormone receptor (GnRHR) gene cause normosmic idiopathic hypogonadotropic hypogonadism (IHH). At least 19 different mutations have been identified in this G-protein-coupled receptor, which consist mostly of missense mutations.
To identify and determine the frequency of mutations in the coding region of the gonadotropin-releasing hormone receptor (GnRHR) gene in forty Chinese patients with normosmic idiopathic hypogonadotropic hypogonadism (IHH) and establish genotype/phenotype correlations where possible.
The diagnosis of HH was based on absent or incomplete sexual development after 17 years of age in girls and 18 years in boys 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. Forty IHH patients and 40 controls were screened for mutations in the coding sequence of the GnRHR gene. The coding region of the GnRHR gene was amplified by PCR and directly sequenced.
A missense mutation, serine 168 arginine (S168R), located in the fourth transmembrane domain of the GnRHR gene, was identified as being in a homozygous state in one male with complete HH. The S168R mutation has been previously shown to be a cause in the complete loss of receptor function because hormone binding to the receptor is completely impaired. In another patient, a compound heterozygous mutation (Gln106Arg and Arg262Gln) was identified in a male with partial HH. The Gln106Arg mutation is located in the first extracellular loop of GnRH-R, this mutation decreases but not does eliminate GnRH binding; while Arg262Gln mutation is located in the third extracellular loop of GnRH-R and only decreases signal transduction. A good correlation between genotype and phenotype was found in our patients. The patient, who was homozygous for the completely inactivating S168R mutation, had complete HH. In addition, the affected patient who was compound heterozygous for the Glnl06Arg--Arg262Gln mutations - has partial HH.
GnRHR mutations can be classified into partial or complete loss of function mutations. Partially inactivating substitutions of the GnRHR frequently found in familial hypogonadotrophic hypogonadism are Q106R and R262Q. Comparison of compound heterozygous with homozygous patients suggests that their phenotype and the response to GnRH is determined by the GnRHR variant with the less severe loss of function.
促性腺激素释放激素受体（GnRHR）基因的人类突变会导致嗅觉正常的特发性低促性腺激素性性腺功能减退（IHH）。在这个G蛋白偶联受体中已鉴定出至少19种不同的突变，其中大多数为错义突变。
鉴定40例嗅觉正常的特发性低促性腺激素性性腺功能减退（IHH）中国患者促性腺激素释放激素受体（GnRHR）基因编码区的突变并确定其频率，并尽可能建立基因型/表型相关性。
HH的诊断基于女孩17岁后、男孩18岁后性发育缺失或不完全，同时伴有男女两性LH水平低或正常，男性睾酮水平低以及女性雌二醇水平低。所有患者在嗅觉特异性测试中嗅觉正常。对40例IHH患者和40例对照进行GnRHR基因编码序列的突变筛查。通过PCR扩增GnRHR基因的编码区并直接测序。
在一名完全性HH男性患者中，发现位于GnRHR基因第四跨膜结构域的一个错义突变，丝氨酸168精氨酸（S168R）呈纯合状态。先前已证明S168R突变是受体功能完全丧失的原因，因为激素与受体的结合完全受损。在另一名患者中，在一名部分性HH男性患者中鉴定出复合杂合突变（Gln106Arg和Arg262Gln）。Gln106Arg突变位于GnRH-R的第一个细胞外环，该突变会降低但不会消除GnRH结合；而Arg262Gln突变位于GnRH-R的第三个细胞外环，只会降低信号转导。在我们的患者中发现基因型与表型之间存在良好的相关性。携带完全失活的S168R突变纯合子的患者患有完全性HH。此外，携带Gln106Arg-Arg262Gln突变复合杂合子的患病患者患有部分性HH。
GnRHR突变可分为功能部分或完全丧失突变。在家族性低促性腺激素性性腺功能减退中常见的GnRHR部分失活替代是Q106R和R262Q。复合杂合子与纯合子患者的比较表明，他们的表型以及对GnRH的反应由功能丧失较轻的GnRHR变体决定。
