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A loss-of-function homozygous mutation in DDX59 implicates a conserved DEAD-box RNA helicase in nervous system development and function

2017; Wiley; Volume: 39; Issue: 2 Linguagem: Inglês

10.1002/humu.23368

1098-1004

Vincenzo Salpietro, Stéphanie Efthymiou, Andreea Manole, Bhawana Maurya, Sarah Wiethoff, Balasubramaniem Ashokkumar, Maria Concetta Cutrupi, Valeria Dipasquale, Sara Manti, Juan A. Botía, Mina Ryten, Jana Vandrovcová, Oscar D. Bello, Conceição Bettencourt, Kshitij Mankad, Ashim Mukherjee, Mousumi Mutsuddi, Henry Houlden,

RNA regulation and disease

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.