%0 Journal Article %J Am J Hum Genet %D 2017 %T De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder. %A Lessel, Davor %A Schob, Claudia %A Küry, Sébastien %A Reijnders, Margot R F %A Harel, Tamar %A Eldomery, Mohammad K %A Coban-Akdemir, Zeynep %A Denecke, Jonas %A Edvardson, Shimon %A Colin, Estelle %A Stegmann, Alexander P A %A Gerkes, Erica H %A Tessarech, Marine %A Bonneau, Dominique %A Barth, Magalie %A Besnard, Thomas %A Cogné, Benjamin %A Revah-Politi, Anya %A Strom, Tim M %A Rosenfeld, Jill A %A Yang, Yaping %A Posey, Jennifer E %A Immken, Ladonna %A Oundjian, Nelly %A Helbig, Katherine L %A Meeks, Naomi %A Zegar, Kelsey %A Morton, Jenny %A Schieving, Jolanda H %A Claasen, Ana %A Huentelman, Matthew %A Narayanan, Vinodh %A Ramsey, Keri %A Brunner, Han G %A Elpeleg, Orly %A Mercier, Sandra %A Bézieau, Stéphane %A Kubisch, Christian %A Kleefstra, Tjitske %A Kindler, Stefan %A Lupski, James R %A Kreienkamp, Hans-Jürgen %K Adenosine Triphosphatases %K Adolescent %K Amino Acids %K Cell Line %K Cell Line, Tumor %K Central Nervous System %K Child %K Child, Preschool %K Developmental Disabilities %K Female %K HEK293 Cells %K Humans %K Intellectual Disability %K Male %K Mutation, Missense %K RNA %K RNA Helicases %X

DHX30 is a member of the family of DExH-box helicases, which use ATP hydrolysis to unwind RNA secondary structures. Here we identified six different de novo missense mutations in DHX30 in twelve unrelated individuals affected by global developmental delay (GDD), intellectual disability (ID), severe speech impairment and gait abnormalities. While four mutations are recurrent, two are unique with one affecting the codon of one recurrent mutation. All amino acid changes are located within highly conserved helicase motifs and were found to either impair ATPase activity or RNA recognition in different in vitro assays. Moreover, protein variants exhibit an increased propensity to trigger stress granule (SG) formation resulting in global translation inhibition. Thus, our findings highlight the prominent role of translation control in development and function of the central nervous system and also provide molecular insight into how DHX30 dysfunction might cause a neurodevelopmental disorder.

%B Am J Hum Genet %V 101 %P 716-724 %8 2017 Nov 02 %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/29100085?dopt=Abstract %R 10.1016/j.ajhg.2017.09.014 %0 Journal Article %J Am J Hum Genet %D 2017 %T Mutations in EBF3 Disturb Transcriptional Profiles and Cause Intellectual Disability, Ataxia, and Facial Dysmorphism. %A Harms, Frederike Leonie %A Girisha, Katta M %A Hardigan, Andrew A %A Kortüm, Fanny %A Shukla, Anju %A Alawi, Malik %A Dalal, Ashwin %A Brady, Lauren %A Tarnopolsky, Mark %A Bird, Lynne M %A Ceulemans, Sophia %A Bebin, Martina %A Bowling, Kevin M %A Hiatt, Susan M %A Lose, Edward J %A Primiano, Michelle %A Chung, Wendy K %A Juusola, Jane %A Akdemir, Zeynep C %A Bainbridge, Matthew %A Charng, Wu-Lin %A Drummond-Borg, Margaret %A Eldomery, Mohammad K %A El-Hattab, Ayman W %A Saleh, Mohammed A M %A Bézieau, Stéphane %A Cogné, Benjamin %A Isidor, Bertrand %A Küry, Sébastien %A Lupski, James R %A Myers, Richard M %A Cooper, Gregory M %A Kutsche, Kerstin %K Adolescent %K Adult %K Amino Acid Substitution %K Ataxia %K Child %K Child, Preschool %K Chromatin %K Cyclin-Dependent Kinase Inhibitor p21 %K Developmental Disabilities %K Exome %K Face %K Female %K Gene Expression Regulation %K Genes, Reporter %K HEK293 Cells %K Humans %K Intellectual Disability %K Language Development Disorders %K Male %K Models, Molecular %K Mosaicism %K Mutation %K Neurodevelopmental Disorders %K Protein Transport %K Syndrome %K Transcription Factors %K Transcription, Genetic %X

From a GeneMatcher-enabled international collaboration, we identified ten individuals affected by intellectual disability, speech delay, ataxia, and facial dysmorphism and carrying a deleterious EBF3 variant detected by whole-exome sequencing. One 9-bp duplication and one splice-site, five missense, and two nonsense variants in EBF3 were found; the mutations occurred de novo in eight individuals, and the missense variant c.625C>T (p.Arg209Trp) was inherited by two affected siblings from their healthy mother, who is mosaic. EBF3 belongs to the early B cell factor family (also known as Olf, COE, or O/E) and is a transcription factor involved in neuronal differentiation and maturation. Structural assessment predicted that the five amino acid substitutions have damaging effects on DNA binding of EBF3. Transient expression of EBF3 mutant proteins in HEK293T cells revealed mislocalization of all but one mutant in the cytoplasm, as well as nuclear localization. By transactivation assays, all EBF3 mutants showed significantly reduced or no ability to activate transcription of the reporter gene CDKN1A, and in situ subcellular fractionation experiments demonstrated that EBF3 mutant proteins were less tightly associated with chromatin. Finally, in RNA-seq and ChIP-seq experiments, EBF3 acted as a transcriptional regulator, and mutant EBF3 had reduced genome-wide DNA binding and gene-regulatory activity. Our findings demonstrate that variants disrupting EBF3-mediated transcriptional regulation cause intellectual disability and developmental delay and are present in ∼0.1% of individuals with unexplained neurodevelopmental disorders.

%B Am J Hum Genet %V 100 %P 117-127 %8 2017 Jan 05 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/28017373?dopt=Abstract %R 10.1016/j.ajhg.2016.11.012