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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism
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GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism

机译:特发性性腺功能减退性腺功能减退症患者的GNRH1突变

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摘要

Idiopathic hypogonadotropic hypogonadism (IHH) is a condition characterized by failure to undergo puberty in the setting of low sex steroids and low gonadotropins. IHH is due to abnormal secretion or action of the master reproductive hormone gonadotropin-releasing hormone (GnRH). Several genes have been found to be mutated in patients with IHH, yet to date no mutations have been identified in the most obvious candidate gene, GNRH1 itself, which encodes the preprohormone that is ultimately processed to produce GnRH. We screened DNA from 310 patients with normosmic IHH (nIHH) and 192 healthy control subjects for sequence changes in CNRH1. In 1 patient with severe congenital nIHH (with micropenis, bilateral cryptorchid-ism, and absent puberty), a homozygous frameshift mutation that is predicted to disrupt the 3 C-terminal amino acids of the GnRH decapeptide and to produce a premature stop codon was identified. Heterozygous variants not seen in controls were identified in 4 patients with nIHH: 1 nonsynonymous missense mutation in the eighth amino acid of the GnRH decapeptide, 1 nonsense mutation that causes premature termination within the GnRH-associated pep-tide (GAP), which lies C-terminal to the GnRH decapeptide within the GnRH precursor, and 2 sequence variants that cause nonsynonymous amino-acid substitutions in the signal peptide and in GnRH-associated peptide. Our results establish mutations in GNRH1 as a genetic cause of nIHH.
机译:特发性性腺功能低下性腺机能减退(IHH)是一种以低性类固醇和低促性腺激素为背景无法进入青春期的疾病。 IHH是由于主要生殖激素促性腺激素释放激素(GnRH)的异常分泌或作用引起的。已发现IHH患者中有几个基因发生了突变,但迄今为止,尚未在最明显的候选基因GNRH1本身中鉴定出突变,该基因编码最终被加工成GnRH的前激素。我们从310名正常IHH(nIHH)患者和192名健康对照受试者中筛选了CNRH1序列变化的DNA。在1名患有严重先天性nIHH(伴有微阴茎,双侧隐睾症和青春期缺乏)的患者中,鉴定出纯合子移码突变,该突变预计会破坏GnRH十肽的3个C末端氨基酸并产生过早的终止密码子。 。在4名患有nIHH的患者中发现了在对照中未发现的杂合变异:在GnRH十肽的第八个氨基酸中有1个非同义错义突变,在GnRH相关肽肽(GAP)中导致1个无义突变导致过早终止,位于C -在GnRH前体中的GnRH十肽的末端-和2个序列变体,其引起信号肽和与GnRH相关的肽中的非同义氨基酸取代。我们的研究结果确定GNRH1突变是nIHH的遗传原因。

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    Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Massachusetts General Hospital, 55 Fruit Street, BHX 5, Boston, MA 02114 Department of Medicine, Division of Endocrinology, Children's Hospital Boston, 333 Longwood Avenue, 6th Floor, Boston, MA 02115;

    Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Massachusetts General Hospital, 55 Fruit Street, BHX 5, Boston, MA 02114;

    Pediatric Endocrine Unit, University Children's Hospital Zurich, Steinwiesstrasse 75, 8032 Zurich, Switzerland;

    Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Massachusetts General Hospital, 55 Fruit Street, BHX 5, Boston, MA 02114;

    Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Massachusetts General Hospital, 55 Fruit Street, BHX 5, Boston, MA 02114;

    Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Massachusetts General Hospital, 55 Fruit Street, BHX 5, Boston, MA 02114;

    Department of Pathology, University Hospital Zurich, Schmelzbergstrasse 12, 8091 Zurich, Switzerland;

    Department of Medicine, Division of Endocrinology, Centre Hospitalier de I'Universite de Montreal, 1058 St-Denis, Montreal, QC, Canada H2X 3J4 PROCREA Cliniques, Montreal, QC, Canada H4P 2R2;

    2500 Nesconset Highway, #12C, Stony Brook, NY 11790;

    Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Massachusetts General Hospital, 55 Fruit Street, BHX 5, Boston, MA 02114;

    Division of General Internal Medicine, University of Washington Medical Center, Campus Box 356429, 1959 NE Pacific Street, Seattle, WA 98195;

    Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Massachusetts General Hospital, 55 Fruit Street, BHX 5, Boston, MA 02114;

    Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Massachusetts General Hospital, 55 Fruit Street, BHX 5, Boston, MA 02114;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    GnRH; luteinizing hormone-releasing hormone; LHRH;

    机译:GnRH;黄体生成素释放激素LHRH;

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