De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder

Davor Lessel; Claudia Schob; Sebastien Kuery; Margot R. F. Reinders; Tamar Harel; Mohammad K. Eldomery; Zeynep Coban-Akdemir; Jonas Denecke; Shimon Edvardson; Estelle Colin; Alexander P. A. Stegmann; Erica H. Gerkes; Marine Tessarech; Dominique Bonneau; Magalie Barth; Thomas Besnard; Benjamin Cogne; Anya Revah-Politi; Tim M. Strom; Jill A. Rosenfeld; Yaping Yang; Jennifer E. Posey; LaDonna Immken; Nelly Oundjian; Katherine L. Helbig; Naomi Meeks; Kelsey Zegar; Jenny Morton; Jolanda H. Schieving; Ana Claasen; Matthew Huentelman; Vinodh Narayanan; Keri Ramsey; Han G. Brunner; Orly Elpeleg; Sandra Mercier; Stephane Bezieau; Christian Kubisch; Tjitske Kleefstra; Stefan Kindler; James R. Lupski; Hans-Juergen Kreienkamp; DDD Study; C4RCD Res Grp

doi:10.1016/j.ajhg.2017.09.014

De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder

Davor Lessel^*, Claudia Schob, Sebastien Kuery, Margot R. F. Reinders, Tamar Harel, Mohammad K. Eldomery, Zeynep Coban-Akdemir, Jonas Denecke, Shimon Edvardson, Estelle Colin, Alexander P. A. Stegmann, Erica H. Gerkes, Marine Tessarech, Dominique Bonneau, Magalie Barth, Thomas Besnard, Benjamin Cogne, Anya Revah-Politi, Tim M. Strom, Jill A. RosenfeldYaping Yang, Jennifer E. Posey, LaDonna Immken, Nelly Oundjian, Katherine L. Helbig, Naomi Meeks, Kelsey Zegar, Jenny Morton, Jolanda H. Schieving, Ana Claasen, Matthew Huentelman, Vinodh Narayanan, Keri Ramsey, Han G. Brunner, Orly Elpeleg, Sandra Mercier, Stephane Bezieau, Christian Kubisch, Tjitske Kleefstra, Stefan Kindler, James R. Lupski, Hans-Juergen Kreienkamp^*, DDD Study, C4RCD Res Grp

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

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.

Original language	English
Pages (from-to)	716-724
Number of pages	9
Journal	American Journal of Human Genetics
Volume	101
Issue number	5
DOIs	https://doi.org/10.1016/j.ajhg.2017.09.014
Publication status	Published - 2 Nov 2017

Keywords

INTELLECTUAL DISABILITY
STRESS GRANULES
RNA GRANULES
PROTEIN
HELICASE
DISEASE
GENE
DISRUPTION
FAMILY
MODULE

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1 Erratum / corrigendum / retractions

De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder (vol 101, pg 716, 2017)
DDD Study & C4RCD Res Grp, 4 Jan 2018, In: American Journal of Human Genetics. 102, 1, p. 196-196 1 p.
Research output: Contribution to journal › Erratum / corrigendum / retractions › Academic

Open Access

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Lessel, D., Schob, C., Kuery, S., Reinders, M. R. F., Harel, T., Eldomery, M. K., Coban-Akdemir, Z., Denecke, J., Edvardson, S., Colin, E., Stegmann, A. P. A., Gerkes, E. H., Tessarech, M., Bonneau, D., Barth, M., Besnard, T., Cogne, B., Revah-Politi, A., Strom, T. M., ... C4RCD Res Grp (2017). De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder. American Journal of Human Genetics, 101(5), 716-724. https://doi.org/10.1016/j.ajhg.2017.09.014

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title = "De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder",

abstract = "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.",

keywords = "INTELLECTUAL DISABILITY, STRESS GRANULES, RNA GRANULES, PROTEIN, HELICASE, DISEASE, GENE, DISRUPTION, FAMILY, MODULE",

author = "Davor Lessel and Claudia Schob and Sebastien Kuery and Reinders, {Margot R. F.} and Tamar Harel and Eldomery, {Mohammad K.} and Zeynep Coban-Akdemir and Jonas Denecke and Shimon Edvardson and Estelle Colin and Stegmann, {Alexander P. A.} and Gerkes, {Erica H.} and Marine Tessarech and Dominique Bonneau and Magalie Barth and Thomas Besnard and Benjamin Cogne and Anya Revah-Politi and Strom, {Tim M.} and Rosenfeld, {Jill A.} and Yaping Yang and Posey, {Jennifer E.} and LaDonna Immken and Nelly Oundjian and Helbig, {Katherine L.} and Naomi Meeks and Kelsey Zegar and Jenny Morton and Schieving, {Jolanda H.} and Ana Claasen and Matthew Huentelman and Vinodh Narayanan and Keri Ramsey and Brunner, {Han G.} and Orly Elpeleg and Sandra Mercier and Stephane Bezieau and Christian Kubisch and Tjitske Kleefstra and Stefan Kindler and Lupski, {James R.} and Hans-Juergen Kreienkamp and {DDD Study} and {C4RCD Res Grp}",

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Lessel, D, Schob, C, Kuery, S, Reinders, MRF, Harel, T, Eldomery, MK, Coban-Akdemir, Z, Denecke, J, Edvardson, S, Colin, E, Stegmann, APA, Gerkes, EH, Tessarech, M, Bonneau, D, Barth, M, Besnard, T, Cogne, B, Revah-Politi, A, Strom, TM, Rosenfeld, JA, Yang, Y, Posey, JE, Immken, L, Oundjian, N, Helbig, KL, Meeks, N, Zegar, K, Morton, J, Schieving, JH, Claasen, A, Huentelman, M, Narayanan, V, Ramsey, K, Brunner, HG, Elpeleg, O, Mercier, S, Bezieau, S, Kubisch, C, Kleefstra, T, Kindler, S, Lupski, JR, Kreienkamp, H-J, DDD Study & C4RCD Res Grp 2017, 'De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder', American Journal of Human Genetics, vol. 101, no. 5, pp. 716-724. https://doi.org/10.1016/j.ajhg.2017.09.014

TY - JOUR

T1 - De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder

AU - Lessel, Davor

AU - Schob, Claudia

AU - Kuery, Sebastien

AU - Reinders, Margot R. F.

AU - Harel, Tamar

AU - Eldomery, Mohammad K.

AU - Coban-Akdemir, Zeynep

AU - Denecke, Jonas

AU - Edvardson, Shimon

AU - Colin, Estelle

AU - Stegmann, Alexander P. A.

AU - Gerkes, Erica H.

AU - Tessarech, Marine

AU - Bonneau, Dominique

AU - Barth, Magalie

AU - Besnard, Thomas

AU - Cogne, Benjamin

AU - Revah-Politi, Anya

AU - Strom, Tim M.

AU - Rosenfeld, Jill A.

AU - Yang, Yaping

AU - Posey, Jennifer E.

AU - Immken, LaDonna

AU - Oundjian, Nelly

AU - Helbig, Katherine L.

AU - Meeks, Naomi

AU - Zegar, Kelsey

AU - Morton, Jenny

AU - Schieving, Jolanda H.

AU - Claasen, Ana

AU - Huentelman, Matthew

AU - Narayanan, Vinodh

AU - Ramsey, Keri

AU - Brunner, Han G.

AU - Elpeleg, Orly

AU - Mercier, Sandra

AU - Bezieau, Stephane

AU - Kubisch, Christian

AU - Kleefstra, Tjitske

AU - Kindler, Stefan

AU - Lupski, James R.

AU - Kreienkamp, Hans-Juergen

AU - DDD Study

AU - C4RCD Res Grp

PY - 2017/11/2

Y1 - 2017/11/2

N2 - 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.

AB - 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.

KW - INTELLECTUAL DISABILITY

KW - STRESS GRANULES

KW - RNA GRANULES

KW - PROTEIN

KW - HELICASE

KW - DISEASE

KW - GENE

KW - DISRUPTION

KW - FAMILY

KW - MODULE

U2 - 10.1016/j.ajhg.2017.09.014

DO - 10.1016/j.ajhg.2017.09.014

M3 - Article

C2 - 29100085

SN - 0002-9297

VL - 101

SP - 716

EP - 724

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 5

ER -

De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder

Abstract

Keywords

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De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder (vol 101, pg 716, 2017)

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