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

SALPIETRO, VINCENZO; EFTHYMIOU, STEPHANIE; MANOLE, ANDREEA; MAURYA, BHAWANA; WIETHOFF, SARAH; ASHOKKUMAR, BALASUBRAMANIEM; CUTRUPI, MARIA CONCETTA; DIPASQUALE, VALERIA; MANTI, SARA; BOTIA, JUAN A.; RYTEN, MINA; VANDROVCOVA, JANA; BELLO, OSCAR D.; BETTENCOURT, CONCEICAO; MANKAD, KSHITIJ; MUKHERJEE, ASHIM; MUTSUDDI, MOUSUMI; HOULDEN, HENRY

HUMAN MUTATION

WILEY-LISS, DIV JOHN WILEY & SONS INC

Lugar: New York; Año: 2018 vol. 39 p. 187 - 192

1059-7794

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.