title: Mutations in DDX59 implicate RNA helicase in the pathogenesis of orofaciodigital syndrome.
abstract: Orofaciodigital syndrome (OFD) is a recognized clinical entity with core defining features in the mouth, face, and digits, in addition to various other features that have been proposed to define distinct subtypes. The three genes linked to OFD-OFD1, TMEM216, and TCTN3-play a role in ciliary biology, a finding consistent with the clinical overlap between OFD and other ciliopathies. Most autosomal-recessive cases of OFD, however, remain undefined genetically. In two multiplex consanguineous Arab families affected by OFD, we identified a tight linkage interval in chromosomal region 1q32.1. Exome sequencing revealed a different homozygous variant in DDX59 in each of the two families, and at least one of the two variants was accompanied by marked reduction in the level of DDX59. DDX59 encodes a relatively uncharacterized member of the DEAD-box-containing RNA helicase family of proteins, which are known to play a critical role in all aspects of RNA metabolism. We show that Ddx59 is highly enriched in its expression in the developing murine palate and limb buds. At the cellular level, we show that DDX59 is localized dynamically to the nucleus and the cytoplasm. Consistent with the absence of DDX59 representation in ciliome databases and our demonstration of its lack of ciliary localization, ciliogenesis appears to be intact in mutant fibroblasts but ciliary signaling appears to be impaired. Our data strongly implicate this RNA helicase family member in the pathogenesis of OFD, although the causal mechanism remains unclear.
authors: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors: Hanan E
authors: HE
authors: Shamseldin
authors: Anna
authors: A
authors: Rajab
authors: Amal
authors: A
authors: Alhashem
authors: Ranad
authors: R
authors: Shaheen
authors: Tarfa
authors: T
authors: Al-Shidi
authors: Rana
authors: R
authors: Alamro
authors: Salma
authors: S
authors: Al Harassi
authors: Fowzan S
authors: FS
authors: Alkuraya
mesh_terms: D000818:Animals; D001483:Base Sequence; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology; D005190:Family; D005260:Female; D018507:Gene Expression Regulation, Developmental; D056426:Genetic Loci / Q000235:genetics; D006801:Humans; D008126:Lod Score; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009958:Orofaciodigital Syndromes / Q000201:enzymology* / Q000235:genetics*; D010375:Pedigree; D020365:RNA Helicases / Q000235:genetics*
chemical_list: C584146:DDX59 protein, human; C584147:DDX59 protein, mouse; D020365:RNA Helicases
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