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Loss of function mutation in LARP7, chaperone of 7SK ncRNA, causes a syndrome of facial dysmorphism, intellectual disability, and primordial dwarfism

Authors

  • Anas M. Alazami,

    1. Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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    • These two authors have contributed equally to this work.

  • Mohammad Al-Owain,

    1. Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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    • These two authors have contributed equally to this work.

  • Fatema Alzahrani,

    1. Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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  • Taghreed Shuaib,

    1. Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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  • Hussain Al-Shamrani,

    1. Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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  • Yahya H. Al-Falki,

    1. Division of Ophthalmology, Department of Surgery, King Khalid University, Abha, Saudi Arabia
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  • Saleh M. Al-Qahtani,

    1. Department of Pediatrics, King Khalid University, Abha, Saudi Arabia
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  • Tarfa Alsheddi,

    1. Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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  • Dilek Colak,

    1. Department of Biostatistics, Epidemiology and Scientific Computing, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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  • Fowzan S. Alkuraya

    Corresponding author
    1. Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
    2. Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
    3. Department of Pediatrics, King Khalid University Hospital and College of Medicine, King Saud University, Riyadh, Saudi Arabia
    • Developmental Genetics Unit, Department of Genetics, King Faisal Specialist Hospital and Research Center, MBC-03 PO BOX 3354, Riyad 11211, Saudi Arabia.
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  • Communicated Garry R. Cutting

Abstract

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.

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