Salpietro, V;
Efthymiou, S;
Manole, A;
Maurya, B;
Wiethoff, S;
Ashokkumar, B;
Cutrupi, MC;
... Houlden, H; + view all
(2017)
A loss-of-function homozygous mutation in DDX59 implicates a conserved DEAD-box RNA helicase in nervous system development and function.
Hum Mutat
10.1002/humu.23368.
(In press).
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Abstract
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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