Reiff Rachel E, Ali Bassam R, Baron Byron, Yu Timothy W, Ben-Salem Salma, Coulter Michael E, Schubert Christian R, Hill R Sean, Akawi Nadia A, Al-Younes Banan, Kaya Namik, Evrony Gilad D, Al-Saffar Muna, Felie Jillian M, Partlow Jennifer N, Sunu Christine M, Schembri-Wismayer Pierre, Alkuraya Fowzan S, Meyer Brian F, Walsh Christopher A, Al-Gazali Lihadh, Mochida Ganeshwaran H
Division of Genetics and Genomics, Department of Medicine Manton Center for Orphan Disease Research and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA Harvard-Massachusetts Institute of Technology (MIT) Division of Health Sciences and Technology, Cambridge, MA 02139, USA.
Department of Pathology, College of Medicine and Health Sciences.
Hum Mol Genet. 2014 Jul 1;23(13):3456-66. doi: 10.1093/hmg/ddu054. Epub 2014 Feb 5.
Whereas many genes associated with intellectual disability (ID) encode synaptic proteins, transcriptional defects leading to ID are less well understood. We studied a large, consanguineous pedigree of Arab origin with seven members affected with ID and mild dysmorphic features. Homozygosity mapping and linkage analysis identified a candidate region on chromosome 17 with a maximum multipoint logarithm of odds score of 6.01. Targeted high-throughput sequencing of the exons in the candidate region identified a homozygous 4-bp deletion (c.169_172delCACT) in the METTL23 (methyltransferase like 23) gene, which is predicted to result in a frameshift and premature truncation (p.His57Valfs*11). Overexpressed METTL23 protein localized to both nucleus and cytoplasm, and physically interacted with GABPA (GA-binding protein transcription factor, alpha subunit). GABP, of which GABPA is a component, is known to regulate the expression of genes such as THPO (thrombopoietin) and ATP5B (ATP synthase, H+ transporting, mitochondrial F1 complex, beta polypeptide) and is implicated in a wide variety of important cellular functions. Overexpression of METTL23 resulted in increased transcriptional activity at the THPO promoter, whereas knockdown of METTL23 with siRNA resulted in decreased expression of ATP5B, thus revealing the importance of METTL23 as a regulator of GABPA function. The METTL23 mutation highlights a new transcriptional pathway underlying human intellectual function.
虽然许多与智力障碍（ID）相关的基因编码突触蛋白，但导致ID的转录缺陷却鲜为人知。我们研究了一个源自阿拉伯的大家系，其中有7名成员患有ID和轻度畸形特征。纯合性定位和连锁分析在17号染色体上确定了一个候选区域，最大多点对数优势分数为6.01。对候选区域外显子进行靶向高通量测序，在METTL23（甲基转移酶样23）基因中发现了一个纯合的4碱基缺失（c.169_172delCACT），预计这会导致移码和过早截断（p.His57Valfs*11）。过表达的METTL23蛋白定位于细胞核和细胞质，并与GABPA（GA结合蛋白转录因子，α亚基）发生物理相互作用。已知GABPA作为组成部分的GABP可调节诸如THPO（血小板生成素）和ATP5B（ATP合酶，H⁺转运，线粒体F1复合体，β多肽）等基因的表达，并参与多种重要的细胞功能。METTL23过表达导致THPO启动子处的转录活性增加，而用小干扰RNA敲低METTL23则导致ATP5B表达降低，从而揭示了METTL23作为GABPA功能调节剂的重要性。METTL23突变突出了人类智力功能背后的一条新的转录途径。
