Cerrato Felecia, Shagoury Jenna, Kralickova Milena, Dwyer Andrew, Falardeau John, Ozata Metin, Van Vliet Guy, Bouloux Pierre, Hall Janet E, Hayes Frances J, Pitteloud Nelly, Martin Kathryn A, Welt Corrine, Seminara Stephanie B
Reproductive Endocrine Unit, Massachusetts General Hospital BHX 504, Fruit Street, Boston, Massachusetts 02114, USA.
Eur J Endocrinol. 2006 Nov;155 Suppl 1:S3-S10. doi: 10.1530/eje.1.02235.
To determine the frequency of rare nucleotide variants in GNRHR and GPR54 in a large cohort of probands (n = 166) with normosmic idiopathic hypogonadotropic hypogonadism (nIHH), characterized by mode of inheritance, testicular volume, and presence or absence of endogenous LH pulsations.
Whenever possible, probands answered detailed questionnaires, underwent full physical exams, and underwent q 10-min frequent blood sampling for LH. Exons segments for GNRHR and GPR54 were screened for mutations. Nucleotide changes were identified as rare variants if they occurred at less than 1% frequency in an ethnically matched control population.
Sixty-two percent of male probands were classified as sporadic, meaning that no other family members had delayed puberty or nIHH. In contrast, 61% of female probands were from familial pedigrees, with either autosomal dominant or autosomal recessive inheritance. Patients displayed a broad spectrum of disease severity based on testicular size and endogenous LH pulsations. Twenty-four rare variants were identified in GNRHR (within 15 probands) and seven rare variants in GPR54 (within five probands).
Rare variants in GNRHR are more common than GPR54 in a nIHH population.
在一大群以遗传方式、睾丸体积以及内源性促黄体生成素（LH）脉冲的有无为特征的嗅觉正常的特发性低促性腺激素性性腺功能减退症（nIHH）先证者（n = 166）中，确定促性腺激素释放激素受体（GNRHR）和G蛋白偶联受体54（GPR54）中罕见核苷酸变异的频率。
只要有可能，先证者需回答详细问卷，接受全面体检，并每10分钟进行一次频繁的LH血样采集。对GNRHR和GPR54的外显子片段进行突变筛查。如果核苷酸变化在种族匹配的对照人群中出现频率低于1%，则将其鉴定为罕见变异。
62%的男性先证者被归类为散发性，这意味着没有其他家庭成员有青春期延迟或nIHH。相比之下，61%的女性先证者来自家族谱系，具有常染色体显性或常染色体隐性遗传。根据睾丸大小和内源性LH脉冲，患者表现出广泛的疾病严重程度。在GNRHR中鉴定出24个罕见变异（在15名先证者中），在GPR54中鉴定出7个罕见变异（在5名先证者中）。
在nIHH人群中，GNRHR中的罕见变异比GPR54更常见。
