Salpietro, V., Efthymiou, S., Manole, A., Maurya, B., Wiethoff, S., Ashokkumar, B., Cutrupi, M.C., Dipasquale, V., Manti, S., Botia, J.A., Ryten, M., Vandrovcova, J., Bello, O.D., Bettencourt, C., Mankad, K., Mukherjee, A., Mutsuddi, M., Houlden, H. (2018). A loss-of-function homozygous mutation in DDX59 implicates a conserved DEAD-box RNA helicase in nervous system development and function.  Human Mutation 39(2): 187--192.

FBrf0237726

Research paper

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.

PMC5814734 (PMC) (EuropePMC)