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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Mental retardation linked to mutations in the HSD17B10 gene interfering with neurosteroid and isoleucine metabolism
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Mental retardation linked to mutations in the HSD17B10 gene interfering with neurosteroid and isoleucine metabolism

机译：智力低下与HSD17B10基因突变干扰神经类固醇和异亮氨酸代谢有关

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摘要

Mutations in the H5D17B10gene were identified in two previously described mentally retarded males. A point mutation c.776G > C was found from a survivor (SV), whereas a potent mutation, c.419C>T, was identified in another deceased case (SF) with un-detectable hydroxysteroid (17β) dehydrogenase 10 (HSD10) activity. Protein levels of mutant H5D10(R130C) in patient SF and HSD10(E249Q) in patient SV were about half that of HSD10 in normal controls. The E249Q mutation appears to affect HSD10 subunit interactions, resulting in an allosteric regulatory enzyme. For catalyzing the oxidation of allopregnanolone by NAD~+ the Hill coefficient of the mutant enzyme is ≈1.3. HSD10(E249Q) was unable to catalyze the dehydrogenation of 2-methyl-3-hydroxy-butyryl-CoA and the oxidation of allopregnanolone, a positive modulator of the γ-aminobutyric acid type A receptor, at low substrate concentrations. Neurosteroid homeostasis is critical for normal cognitive development, and there is increasing evidence that a blockade of isoleucine catabolism alone does not commonly cause developmental disabilities. The results support the theory that an imbalance in neurosteroid metabolism could be a major cause of the neurological handicap associated with hydroxysteroid (17β) dehydrogenase 10 deficiency.
机译：H5D17B10基因的突变已在两名先前描述的弱智男性中鉴定出。从幸存者（SV）中发现了点突变c.776G> C，而在另一例死者（SF）中发现了有效突变c.419C> T，其中存在不可检测的羟类固醇（17β）脱氢酶10（HSD10）活动。 SF患者中的突变H5D10（R130C）和SV患者中的HSD10（E249Q）的蛋白质水平约为正常对照中HSD10的一半。 E249Q突变似乎影响HSD10亚基的相互作用，导致变构调节酶。为了催化NAD〜+催化去甲泼尼龙的氧化，突变酶的希尔系数约为1.3。 HSD10（E249Q）在低底物浓度下无法催化2-甲基-3-羟基-丁酰基-CoA的脱氢反应和丙型戊四醇酮（γ-氨基丁酸A型受体的正调节剂）的氧化。神经类固醇稳态对于正常的认知发育至关重要，越来越多的证据表明，仅阻断异亮氨酸分解代谢通常不会导致发育障碍。该结果支持以下理论：神经类固醇代谢失衡可能是与羟基类固醇（17β）脱氢酶10缺乏症相关的神经障碍的主要原因。

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    Song-Yu Yang; Xue-Ying He; Simon E. Olpin; Vernon R. Sutton; Joe McMenamin; Manfred Philipp; Robert B. Denman; Mazhar Malik;

  • 作者单位

    Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314;

    Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314;

    Department of Clinical Chemistry, Sheffield Children's Hospital, Sheffield S10 2TH, United Kingdom;

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030;

    Department of Pediatrics, Our Lady's Hospital for Sick Children, Dublin 12, Ireland;

    Department of Chemistry, Lehman College, City University of New York, Bronx, NY 10486;

    Department of Molecular Biology, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314;

    Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314;

  • 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
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  • 关键词

    developmental disabilities; HSD10 deficiency; hydroxyacyl-CoA dehydrogenase;

    机译：发育障碍;HSD10缺乏症;羟酰基辅酶A脱氢酶;

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