Balak, Chris, Benard, Marianne, Schaefer, Elise, Iqbal, Sumaiya, Ramsey, Keri, Ernoult-Lange, Michele, Mattioli, Francesca, Llaci, Lorida, Geoffroy, Veronique, Courel, Maite, Naymik, Marcus, Bachman, Kristine K., Pfundt, Rolph, Rump, Patrick, ter Beest, Johanna, Wentzensen, Ingrid M., Monaghan, Kristin G., McWalter, Kirsty, Richholt, Ryan, Le Bechec, Antony, Jepsen, Wayne, De Both, Matt, Belnap, Newell, Boland, Anne, Piras, Ignazio S., Deleuze, Jean-Francois, Szelinger, Szabolcs, Dollfus, Helene, Chelly, Jamel, Muller, Jean ORCID: 0000-0002-7682-559X, Campbell, Arthur, Lal, Dennis, Rangasamy, Sampathkumar ORCID: 0000-0003-2151-9162, Mandel, Jean-Louis, Narayanan, Vinodh, Huentelman, Matt, Weil, Dominique and Piton, Amelie ORCID: 0000-0003-0408-7468 (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. Am. J. Hum. Genet., 105 (3). S. 509 - 526. CAMBRIDGE: CELL PRESS. ISSN 1537-6605

Full text not available from this repository.

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 fibro-blast 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Balak, ChrisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Benard, MarianneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schaefer, EliseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Iqbal, SumaiyaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ramsey, KeriUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ernoult-Lange, MicheleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mattioli, FrancescaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Llaci, LoridaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Geoffroy, VeroniqueUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Courel, MaiteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Naymik, MarcusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bachman, Kristine K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pfundt, RolphUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rump, PatrickUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
ter Beest, JohannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wentzensen, Ingrid M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Monaghan, Kristin G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McWalter, KirstyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Richholt, RyanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Le Bechec, AntonyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jepsen, WayneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Both, MattUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Belnap, NewellUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boland, AnneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Piras, Ignazio S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Deleuze, Jean-FrancoisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Szelinger, SzabolcsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dollfus, HeleneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chelly, JamelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muller, JeanUNSPECIFIEDorcid.org/0000-0002-7682-559XUNSPECIFIED
Campbell, ArthurUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lal, DennisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rangasamy, SampathkumarUNSPECIFIEDorcid.org/0000-0003-2151-9162UNSPECIFIED
Mandel, Jean-LouisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Narayanan, VinodhUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Huentelman, MattUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weil, DominiqueUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Piton, AmelieUNSPECIFIEDorcid.org/0000-0003-0408-7468UNSPECIFIED
URN: urn:nbn:de:hbz:38-141717
DOI: 10.1016/j.ajhg.2019.07.010
Journal or Publication Title: Am. J. Hum. Genet.
Volume: 105
Number: 3
Page Range: S. 509 - 526
Date: 2019
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 1537-6605
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
TRANSLATIONAL REPRESSION; COMMON-CAUSE; MUTATIONS; COMPLEX; PROTEINS; REVEALS; METABOLISM; DENDRITES; FRAMEWORK; NEURONSMultiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/14171

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item