A specific mutation in TBL1XR1 causes Pierpont syndrome.
A specific mutation in TBL1XR1 causes Pierpont syndrome.
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DOI：
10.1136/jmedgenet-2015-103233
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发表时间：
2016-05
影响因子：
4
通讯作者：
Hennekam RC
中科院分区：
文献类型：
--
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
发育迟缓、面部特征、听力丧失以及四肢远端脂肪分布异常相结合的情况被称为皮尔庞特综合征。本研究的目的是检测和研究皮尔庞特综合征的病因。
我们采用全外显子组测序分析了4名无亲缘关系的皮尔庞特综合征患者，并对另外2名无亲缘关系的患者进行了桑格测序。在人类尸检大脑标本、脂肪组织、肌肉和肝脏中分析了野生型候选基因的信使核糖核酸（mRNA）表达情况。还分析了患者和对照组淋巴细胞中的核糖核酸（RNA）表达。变异蛋白在人胚肾293（HEK293）细胞中表达并纯化，以评估其对蛋白质折叠和功能的影响。
我们在转导蛋白β样1 X连锁受体1（TBL1XR1）中鉴定出一个单一的杂合错义变异，即c.1337A>C（p.Tyr446Cys），它是所有患者的致病原因。在垂体、下丘脑、白色和棕色脂肪组织、肌肉和肝脏中都证实了TBL1XR1 mRNA的表达。与4名对照组相比，2名患者淋巴细胞中的mRNA表达较低。突变的TBL1XR1蛋白正确组装到核受体共抑制因子（NCoR）/视黄酸和甲状腺受体沉默中介体（SMRT）复合物中，这表明是一种显性负性机制。这与已被认为与自闭症有关的生殖系TBL1XR1功能缺失性缺失以及其他TBL1XR1突变形成对比。然而，皮尔庞特综合征患者不存在自闭症。
这项研究确定了一个特定的TBL1XR1突变是皮尔庞特综合征的病因。TBL1XR1的缺失和其他突变可导致自闭症。具有p.Tyr446Cys突变的皮尔庞特患者与具有其他突变和整个基因缺失的个体之间的显著差异表明，TBL1XR1 p.Tyr446Cys突变存在一种特定但尚未明确的疾病机制。
The combination of developmental delay, facial characteristics, hearing loss and abnormal fat distribution in the distal limbs is known as Pierpont syndrome. The aim of the present study was to detect and study the cause of Pierpont syndrome. We used whole-exome sequencing to analyse four unrelated individuals with Pierpont syndrome, and Sanger sequencing in two other unrelated affected individuals. Expression of mRNA of the wild-type candidate gene was analysed in human postmortem brain specimens, adipose tissue, muscle and liver. Expression of RNA in lymphocytes in patients and controls was additionally analysed. The variant protein was expressed in, and purified from, HEK293 cells to assess its effect on protein folding and function. We identified a single heterozygous missense variant, c.1337A>C (p.Tyr446Cys), in transducin β-like 1 X-linked receptor 1 (TBL1XR1) as disease-causing in all patients. TBL1XR1 mRNA expression was demonstrated in pituitary, hypothalamus, white and brown adipose tissue, muscle and liver. mRNA expression is lower in lymphocytes of two patients compared with the four controls. The mutant TBL1XR1 protein assembled correctly into the nuclear receptor corepressor (NCoR)/ silencing mediator for retinoid and thyroid receptors (SMRT) complex, suggesting a dominant-negative mechanism. This contrasts with loss-of-function germline TBL1XR1 deletions and other TBL1XR1 mutations that have been implicated in autism. However, autism is not present in individuals with Pierpont syndrome. This study identifies a specific TBL1XR1 mutation as the cause of Pierpont syndrome. Deletions and other mutations in TBL1XR1 can cause autism. The marked differences between Pierpont patients with the p.Tyr446Cys mutation and individuals with other mutations and whole gene deletions indicate a specific, but as yet unknown, disease mechanism of the TBL1XR1 p.Tyr446Cys mutation.