Heinen Charlotte A, Jongejan Aldo, Watson Peter J, Redeker Bert, Boelen Anita, Boudzovitch-Surovtseva Olga, Forzano Francesca, Hordijk Roel, Kelley Richard, Olney Ann H, Pierpont Mary Ella, Schaefer G Bradley, Stewart Fiona, van Trotsenburg A S Paul, Fliers Eric, Schwabe John W R, Hennekam Raoul C
Department of Endocrinology and Metabolism, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands Department of Paediatric Endocrinology, Emma Children's Hospital, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
J Med Genet. 2016 May;53(5):330-7. doi: 10.1136/jmedgenet-2015-103233. Epub 2016 Jan 14.
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>G (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.
发育迟缓、面部特征、听力丧失和远端肢体脂肪分布异常的组合被称为皮尔庞特综合征。本研究的目的是检测并研究皮尔庞特综合征的病因。
我们使用全外显子组测序分析了4名患有皮尔庞特综合征的无关个体，并对另外2名无关的受影响个体进行了桑格测序。在人类尸检脑标本、脂肪组织、肌肉和肝脏中分析了野生型候选基因的mRNA表达。此外，还分析了患者和对照淋巴细胞中的RNA表达。将变异蛋白在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。
我们在转导素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，c.1337A>G（p.Tyr446Cys），在所有患者中均为致病原因。TBL1XR1 mRNA表达在垂体、下丘脑、白色和棕色脂肪组织、肌肉和肝脏中得到证实。与4名对照相比，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）/类视黄醇和甲状腺受体沉默介质（SMRT）复合物中，提示存在显性负性机制。这与功能丧失的种系TBL1XR1缺失和其他与自闭症有关的TBL1XR1突变形成对比。然而，皮尔庞特综合征患者不存在自闭症。
本研究确定了一种特定的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。携带p.Tyr446Cys突变的皮尔庞特患者与其他突变和全基因缺失个体之间的显著差异表明TBL1XR1 p.Tyr446Cys突变存在特定但尚未明确的疾病机制。
