These two authors have contributed equally to this work.
Loss of function mutation in LARP7, chaperone of 7SK ncRNA, causes a syndrome of facial dysmorphism, intellectual disability, and primordial dwarfism†
Article first published online: 30 AUG 2012
© 2012 Wiley Periodicals, Inc.
Volume 33, Issue 10, pages 1429–1434, October 2012
How to Cite
Alazami, A. M., Al-Owain, M., Alzahrani, F., Shuaib, T., Al-Shamrani, H., Al-Falki, Y. H., Al-Qahtani, S. M., Alsheddi, T., Colak, D. and Alkuraya, F. S. (2012), Loss of function mutation in LARP7, chaperone of 7SK ncRNA, causes a syndrome of facial dysmorphism, intellectual disability, and primordial dwarfism. Hum. Mutat., 33: 1429–1434. doi: 10.1002/humu.22175
Communicated Garry R. Cutting
- Issue published online: 13 SEP 2012
- Article first published online: 30 AUG 2012
- Accepted manuscript online: 3 AUG 2012 02:05PM EST
- Manuscript Accepted: 19 JUL 2012
- Manuscript Received: 30 MAR 2012
- King Faisal Specialist Hospital and Research Centre. Grant Number: RAC no. 2080006
- KACST. Grant Number: 09-MED941-20 to F.S.A.
- DHFMR Collaborative Grant (to F.S.A.)
- primordial dwarfism;
Primordial dwarfism (PD) is a clinically and genetically heterogeneous condition. Various molecular mechanisms are known to underlie the disease including impaired mitotic mechanics, abnormal IGF2 expression, perturbed DNA damage response, defective spliceosomal machinery, and abnormal replication licensing. Here, we describe a syndromic form of PD associated with severe intellectual disability and distinct facial features in a large multiplex Saudi family. Analysis reveals a novel underlying mechanism for PD involving depletion of 7SK, an abundant cellular noncoding RNA (ncRNA), due to mutation of its chaperone LARP7. We show that 7SK levels are tightly linked to LARP7 expression across cell lines, and that this chaperone is ubiquitously expressed in the mouse embryo. The 7SK is known to influence the expression of a wide array of genes through its inhibitory effect on the positive transcription elongation factor b (P-TEFb) as well as its competing role in HMGA1-mediated transcriptional regulation. This study documents a critical role played by ncRNA in human development and adds to the growing list of molecular mechanisms that, when perturbed, converge on the PD phenotype. Hum Mutat 33:1429–1434, 2012. © 2012 Wiley Periodicals, Inc.