期刊
HUMAN MOLECULAR GENETICS
卷 23, 期 13, 页码 3456-3466出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddu054
关键词
-
资金
- National Institute of Neurological Disorders and Stroke [2R01NS035129]
- National Institute of Mental Health [R01MH083565, 1F30MH702909-01]
- Fogarty International Center [R21TW008223]
- Simons Foundation
- Dubai Harvard Foundation for Medical Research
- Manton Center for Orphan Disease Research
- National Institute of General Medical Sciences [T32GM007753]
- National Institutes of Health [T32NS007484-08]
- Clinical Investigator Training Program at Harvard-MIT Health Sciences and Technology
- Beth Israel Deaconess Medical Center
- Pfizer, Inc.
- Merck Co., Inc.
- Nancy Lurie Marks Junior Faculty MeRIT Fellowship
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据