Journal
HUMAN MUTATION
Volume 39, Issue 2, Pages 187-192Publisher
WILEY
DOI: 10.1002/humu.23368
Keywords
DEAD-box RNA Helicase; DDX59; mahe; leukoencephalopathy; NOTCH signaling; Sonic Hedgehog signaling
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Funding
- Synaptopathies Wellcome Trust in equipment and strategic award [WT093205MA, WT104033AIA]
- Medical Research Council [G0802462, MR/K01417X/1, MR/N008324/1] Funding Source: researchfish
- Muscular Dystrophy UK [16GRO-PS36-0055] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0515-10082, ACF-2012-17-017] Funding Source: researchfish
- MRC [G0802462, MR/N008324/1, MR/K01417X/1] Funding Source: UKRI
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We report on a homozygous frameshift deletion in DDX59 (c.185del: p.Phe62fs*13) in a family presenting with orofaciodigital syndrome phenotype associated with a broad neurological involvement characterized by microcephaly, intellectual disability, epilepsy, and white matter signal abnormalities associated with cortical and subcortical ischemic events. DDX59 encodes a DEAD-box RNA helicase and its role in brain function and neurological diseases is unclear. We showed a reduction of mutant cDNA and perturbation of SHH signaling from patient-derived cell lines; furthermore, analysis of human brain gene expression provides evidence that DDX59 is enriched in oligodendrocytes and might act within pathways of leukoencephalopathies-associated genes. We also characterized the neuronal phenotype of the Drosophila model using mutant mahe, the homolog of human DDX59, and showed that mahe loss-of-function mutant embryos exhibit impaired development of peripheral and central nervous system. Taken together, our results support a conserved role of this DEAD-box RNA helicase in neurological function.
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