title: Loss of function mutation in LARP7, chaperone of 7SK ncRNA, causes a syndrome of facial dysmorphism, intellectual disability, and primordial dwarfism.
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.
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Anas M
authors.initials: AM
authors.lastname: Alazami
authors.forename: Mohammad
authors.initials: M
authors.lastname: Al-Owain
authors.forename: Fatema
authors.initials: F
authors.lastname: Alzahrani
authors.forename: Taghreed
authors.initials: T
authors.lastname: Shuaib
authors.forename: Hussain
authors.initials: H
authors.lastname: Al-Shamrani
authors.forename: Yahya H
authors.initials: YH
authors.lastname: Al-Falki
authors.forename: Saleh M
authors.initials: SM
authors.lastname: Al-Qahtani
authors.forename: Tarfa
authors.initials: T
authors.lastname: Alsheddi
authors.forename: Dilek
authors.initials: D
authors.lastname: Colak
authors.forename: Fowzan S
authors.initials: FS
authors.lastname: Alkuraya
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D019465:Craniofacial Abnormalities; D004392:Dwarfism / Q000235:genetics* / Q000378:metabolism; D005145:Face / Q000002:abnormalities; D019066:Facies; D005260:Female; D005838:Genotype; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000378:metabolism; D008297:Male; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009133:Muscular Atrophy / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010375:Pedigree; D022661:RNA, Untranslated / Q000737:chemistry* / Q000378:metabolism; D012261:Ribonucleoproteins / Q000235:genetics*; D013577:Syndrome; D055815:Young Adult
chemical_list: C528908:Larp7 protein, human; D018832:Molecular Chaperones; D022661:RNA, Untranslated; D012261:Ribonucleoproteins