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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
Author(s) -
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
Publication year - 2018
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23368
Subject(s) - biology , frameshift mutation , rna helicase a , genetics , microcephaly , mutant , phenotype , mutation , dead box , loss function , gene , rna , helicase
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.