Mutations in TBL1X Are Associated With Central Hypothyroidism.
Mutations in TBL1X Are Associated With Central Hypothyroidism.
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TBL1X中的突变与中央甲状腺功能减退症有关。
DOI：
10.1210/jc.2016-2531
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发表时间：
2016-12
期刊：
影响因子：
--
通讯作者：
van Trotsenburg AS
中科院分区：
文献类型：
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作者：
Heinen CA;Losekoot M;Sun Y;Watson PJ;Fairall L;Joustra SD;Zwaveling-Soonawala N;Oostdijk W;van den Akker EL;Alders M;Santen GW;van Rijn RR;Dreschler WA;Surovtseva OV;Biermasz NR;Hennekam RC;Wit JM;Schwabe JW;Boelen A;Fliers E;van Trotsenburg AS
孤立性先天性中枢性甲状腺功能减退症（CeH）可由TRHR、TSHB和IGSF 1突变引起，但其病因往往仍无法解释。我们在诊断为孤立性CeH的三个亲属中鉴定了转导素β样蛋白1，X连锁（TBL 1X）基因的错义突变。TBL 1X是甲状腺激素受体-辅阻遏物复合物的一部分。该研究的目的是鉴定不明原因的孤立性CeH患者的TBL 1X突变，对受影响个体的亲属进行桑格测序，以及临床和生化表征;体外研究突变的功能后果;以及人下丘脑和垂体中的mRNA表达和免疫染色。这是一项观察性研究。这项研究是在大学医学中心进行的。19名有突变的人和7名没有突变的人参加了这项研究。结果测量包括测序结果，突变携带者的临床和生化特征，以及体外功能和表达研究的结果。桑格测序产生了另外五个突变。所有患者（n = 8; 6名男性）既往均诊断为CeH（游离T4 [FT 4]浓度低于参考区间，正常促甲状腺激素）。11个亲戚（两个男性）也携带突变。一名女性有CeH，而另外10名女性的FT 4浓度低于正常水平。作为一个群体，成年突变携带者的FT 4浓度比对照组低20%-25%。19名接受评估的携带者中有12名患有听力损失。突变位于蛋白质的高度保守的WD 40重复结构域，影响其表达和热稳定性。TBL 1X mRNA和蛋白在人下丘脑和垂体中表达。TBL 1X突变与CeH和听力损失相关。突变携带者的FT 4浓度从正常低水平到与CeH相容的值不等。通过DNA分析、临床和生化表型分析以及体外功能和表达研究，我们发现TBL 1X突变与中枢性甲状腺功能减退和听力损失相关。
Isolated congenital central hypothyroidism (CeH) can result from mutations in TRHR, TSHB, and IGSF1, but its etiology often remains unexplained. We identified a missense mutation in the transducin β-like protein 1, X-linked (TBL1X) gene in three relatives diagnosed with isolated CeH. TBL1X is part of the thyroid hormone receptor-corepressor complex. The objectives of the study were the identification of TBL1X mutations in patients with unexplained isolated CeH, Sanger sequencing of relatives of affected individuals, and clinical and biochemical characterization; in vitro investigation of functional consequences of mutations; and mRNA expression in, and immunostaining of, human hypothalami and pituitary glands. This was an observational study. The study was conducted at university medical centers. Nineteen individuals with and seven without a mutation participated in the study. Outcome measures included sequencing results, clinical and biochemical characteristics of mutation carriers, and results of in vitro functional and expression studies. Sanger sequencing yielded five additional mutations. All patients (n = 8; six males) were previously diagnosed with CeH (free T4 [FT4] concentration below the reference interval, normal thyrotropin). Eleven relatives (two males) also carried mutations. One female had CeH, whereas 10 others had low-normal FT4 concentrations. As a group, adult mutation carriers had 20%–25% lower FT4 concentrations than controls. Twelve of 19 evaluated carriers had hearing loss. Mutations are located in the highly conserved WD40-repeat domain of the protein, influencing its expression and thermal stability. TBL1X mRNA and protein are expressed in the human hypothalamus and pituitary. TBL1X mutations are associated with CeH and hearing loss. FT4 concentrations in mutation carriers vary from low-normal to values compatible with CeH. By using DNA-analysis, clinical and biochemical phenotyping, and in vitro functional and expression studies, we show that TBL1X mutations are associated with central hypothyroidism and hearing loss.
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影响因子：
29
作者：
Kulozik, Philipp;Jones, Allan;Herzig, Stephan
通讯作者：
Herzig, Stephan
影响因子：
4.8
作者：
Monden, T;Wondisford, FE;Hollenberg, AN
通讯作者：
Hollenberg, AN
影响因子：
4
作者：
Heinen CA;Jongejan A;Watson PJ;Redeker B;Boelen A;Boudzovitch-Surovtseva O;Forzano F;Hordijk R;Kelley R;Olney AH;Pierpont ME;Schaefer GB;Stewart F;van Trotsenburg AS;Fliers E;Schwabe JW;Hennekam RC
通讯作者：
Hennekam RC
DOI：
10.1073/pnas.96.5.1959
发表时间：
1999-03-02
影响因子：
11.1
作者：
Fondell, JD;Guermah, M;Roeder, RG
通讯作者：
Roeder, RG
影响因子：
16.8
作者：
通讯作者：
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