Rare De Novo Missense Variants in RNA Helicase DDX6 Cause Intellectual Disability and Dysmorphic Features and Lead to P-Body Defects and RNA Dysregulation - Compartimentation et trafic intracellulaire des mRNP Access content directly
Journal Articles American Journal of Human Genetics Year : 2019

Rare De Novo Missense Variants in RNA Helicase DDX6 Cause Intellectual Disability and Dysmorphic Features and Lead to P-Body Defects and RNA Dysregulation

Chris Balak
  • Function : Author
Sumaiya Iqbal
  • Function : Author
Keri Ramsey
  • Function : Author
Lorida Llaci
  • Function : Author
Marcus Naymik
  • Function : Author
Kristine K Bachman
  • Function : Author
Patrick Rump
  • Function : Author
Johanna ter Beest
  • Function : Author
Kristin G Monaghan
  • Function : Author
Kirsty Mcwalter
Ryan Richholt
  • Function : Author
Antony Le Béchec
  • Function : Author
Wayne Jepsen
  • Function : Author
Matt de Both
  • Function : Author
Newell Belnap
  • Function : Author
Anne Boland
Ignazio S Piras
  • Function : Author
Jean-François Deleuze
  • Function : Author
  • PersonId : 1015006
Szabolcs Szelinger
  • Function : Author
Jean Muller
Arthur Campbell
  • Function : Author
Sampathkumar Rangasamy
  • Function : Author
Vinodh Narayanan
  • Function : Author
Matt Huentelman
  • Function : Author

Abstract

The human RNA helicase DDX6 is an essential component of membrane-less organelles called processing bodies (PBs). PBs are involved in mRNA metabolic processes including translational repression via coordinated storage of mRNAs. Previous studies in human cell lines have implicated altered DDX6 in molecular and cellular dysfunction, but clinical consequences and pathogenesis in humans have yet to be described. Here, we report the identification of five rare de novo missense variants in DDX6 in probands presenting with intellectual disability, developmental delay, and similar dysmorphic features including telecanthus, epicanthus, arched eyebrows, and low-set ears. All five missense variants (p.His372Arg, p.Arg373Gln, p.Cys390Arg, p.Thr391Ile, and p.Thr391Pro) are located in two conserved motifs of the RecA-2 domain of DDX6 involved in RNA binding, helicase activity, and protein-partner binding. We use functional studies to demonstrate that the first variants identified (p.Arg373Gln and p.Cys390Arg) cause significant defects in PB assembly in primary fibroblast and model human cell lines. These variants' interactions with several protein partners were also disrupted in immunoprecipitation assays. Further investigation via complementation assays included the additional variants p.Thr391Ile and p.Thr391Pro, both of which, similarly to p.Arg373Gln and p.Cys390Arg, demonstrated significant defects in P-body assembly. Complementing these molecular findings, modeling of the variants on solved protein structures showed distinct spatial clustering near known protein binding regions. Collectively, our clinical and molecular data describe a neurodevelopmental syndrome associated with pathogenic missense variants in DDX6. Additionally, we suggest DDX6 join the DExD/H-box genes DDX3X and DHX30 in an emerging class of neurodevelopmental disorders involving RNA helicases.
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Dates and versions

hal-02271087 , version 1 (26-11-2020)

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Chris Balak, Marianne Bénard, Elise Schaefer, Sumaiya Iqbal, Keri Ramsey, et al.. Rare De Novo Missense Variants in RNA Helicase DDX6 Cause Intellectual Disability and Dysmorphic Features and Lead to P-Body Defects and RNA Dysregulation. American Journal of Human Genetics, 2019, 105 (3), pp.509-525. ⟨10.1016/j.ajhg.2019.07.010⟩. ⟨hal-02271087⟩
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