Variants in PUS7 Cause Intellectual Disability with Speech Delay, Microcephaly, Short Stature, and Aggressive Behavior

Arjan P.M. de Brouwer; Rami Abou Jamra; Nadine Körtel; Clara Soyris; Daniel L. Polla; Modi Safra; Avia Zisso; Christopher A. Powell; Pedro Rebelo-Guiomar; Nadja Dinges; Violeta Morin; Michael Stock; Mureed Hussain; Mohsin Shahzad; Saima Riazuddin; Zubair M. Ahmed; Rolph Pfundt; Franziska Schwarz; Lonneke de Boer; André Reis; Detilina Grozeva; F. Lucy Raymond; Sheikh Riazuddin; David A. Koolen; Michal Minczuk; Jean Yves Roignant; Hans van Bokhoven; Schraga Schwartz

doi:10.1016/j.ajhg.2018.10.026

Variants in PUS7 Cause Intellectual Disability with Speech Delay, Microcephaly, Short Stature, and Aggressive Behavior

Arjan P.M. de Brouwer, Rami Abou Jamra, Nadine Körtel, Clara Soyris, Daniel L. Polla, Modi Safra, Avia Zisso, Christopher A. Powell, Pedro Rebelo-Guiomar, Nadja Dinges, Violeta Morin, Michael Stock, Mureed Hussain, Mohsin Shahzad, Saima Riazuddin, Zubair M. Ahmed, Rolph Pfundt, Franziska Schwarz, Lonneke de Boer, André ReisDetilina Grozeva, F. Lucy Raymond, Sheikh Riazuddin, David A. Koolen, Michal Minczuk, Jean Yves Roignant, Hans van Bokhoven, Schraga Schwartz

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Abstract

We describe six persons from three families with three homozygous protein truncating variants in PUS7: c.89_90del (p.Thr30Lysfs^∗20), c.1348C>T (p.Arg450^∗), and a deletion of the penultimate exon 15. All these individuals have intellectual disability with speech delay, short stature, microcephaly, and aggressive behavior. PUS7 encodes the RNA-independent pseudouridylate synthase 7. Pseudouridylation is the most abundant post-transcriptional modification in RNA, which is primarily thought to stabilize secondary structures of RNA. We show that the disease-related variants lead to abolishment of PUS7 activity on both tRNA and mRNA substrates. Moreover, pus7 knockout in Drosophila melanogaster results in a number of behavioral defects, including increased activity, disorientation, and aggressiveness supporting that neurological defects are caused by PUS7 variants. Our findings demonstrate that RNA pseudouridylation by PUS7 is essential for proper neuronal development and function.

Original language	English
Pages (from-to)	1045-1052
Number of pages	8
Journal	American Journal of Human Genetics
Volume	103
Issue number	6
DOIs	https://doi.org/10.1016/j.ajhg.2018.10.026
State	Published - 6 Dec 2018
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2018 American Society of Human Genetics

Keywords

Drosophila melanogaster
aggressive behavior
growth delay
intellectual disability
mRNA substrates
microcephaly
neurodevelopmental delay
pseudouridylation
speech delay
tRNA

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10.1016/j.ajhg.2018.10.026

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de Brouwer, A. P. M., Abou Jamra, R., Körtel, N., Soyris, C., Polla, D. L., Safra, M., Zisso, A., Powell, C. A., Rebelo-Guiomar, P., Dinges, N., Morin, V., Stock, M., Hussain, M., Shahzad, M., Riazuddin, S., Ahmed, Z. M., Pfundt, R., Schwarz, F., de Boer, L., ... Schwartz, S. (2018). Variants in PUS7 Cause Intellectual Disability with Speech Delay, Microcephaly, Short Stature, and Aggressive Behavior. American Journal of Human Genetics, 103(6), 1045-1052. https://doi.org/10.1016/j.ajhg.2018.10.026

@article{9373b476e738461b88884302f34ca6c0,

title = "Variants in PUS7 Cause Intellectual Disability with Speech Delay, Microcephaly, Short Stature, and Aggressive Behavior",

abstract = "We describe six persons from three families with three homozygous protein truncating variants in PUS7: c.89_90del (p.Thr30Lysfs∗20), c.1348C>T (p.Arg450∗), and a deletion of the penultimate exon 15. All these individuals have intellectual disability with speech delay, short stature, microcephaly, and aggressive behavior. PUS7 encodes the RNA-independent pseudouridylate synthase 7. Pseudouridylation is the most abundant post-transcriptional modification in RNA, which is primarily thought to stabilize secondary structures of RNA. We show that the disease-related variants lead to abolishment of PUS7 activity on both tRNA and mRNA substrates. Moreover, pus7 knockout in Drosophila melanogaster results in a number of behavioral defects, including increased activity, disorientation, and aggressiveness supporting that neurological defects are caused by PUS7 variants. Our findings demonstrate that RNA pseudouridylation by PUS7 is essential for proper neuronal development and function.",

keywords = "Drosophila melanogaster, aggressive behavior, growth delay, intellectual disability, mRNA substrates, microcephaly, neurodevelopmental delay, pseudouridylation, speech delay, tRNA",

author = "{de Brouwer}, {Arjan P.M.} and {Abou Jamra}, Rami and Nadine K{\"o}rtel and Clara Soyris and Polla, {Daniel L.} and Modi Safra and Avia Zisso and Powell, {Christopher A.} and Pedro Rebelo-Guiomar and Nadja Dinges and Violeta Morin and Michael Stock and Mureed Hussain and Mohsin Shahzad and Saima Riazuddin and Ahmed, {Zubair M.} and Rolph Pfundt and Franziska Schwarz and {de Boer}, Lonneke and Andr{\'e} Reis and Detilina Grozeva and Raymond, {F. Lucy} and Sheikh Riazuddin and Koolen, {David A.} and Michal Minczuk and Roignant, {Jean Yves} and {van Bokhoven}, Hans and Schraga Schwartz",

note = "Publisher Copyright: {\textcopyright} 2018 American Society of Human Genetics",

year = "2018",

month = dec,

day = "6",

doi = "10.1016/j.ajhg.2018.10.026",

language = "אנגלית",

volume = "103",

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de Brouwer, APM, Abou Jamra, R, Körtel, N, Soyris, C, Polla, DL, Safra, M, Zisso, A, Powell, CA, Rebelo-Guiomar, P, Dinges, N, Morin, V, Stock, M, Hussain, M, Shahzad, M, Riazuddin, S, Ahmed, ZM, Pfundt, R, Schwarz, F, de Boer, L, Reis, A, Grozeva, D, Raymond, FL, Riazuddin, S, Koolen, DA, Minczuk, M, Roignant, JY, van Bokhoven, H & Schwartz, S 2018, 'Variants in PUS7 Cause Intellectual Disability with Speech Delay, Microcephaly, Short Stature, and Aggressive Behavior', American Journal of Human Genetics, vol. 103, no. 6, pp. 1045-1052. https://doi.org/10.1016/j.ajhg.2018.10.026

TY - JOUR

T1 - Variants in PUS7 Cause Intellectual Disability with Speech Delay, Microcephaly, Short Stature, and Aggressive Behavior

AU - de Brouwer, Arjan P.M.

AU - Abou Jamra, Rami

AU - Körtel, Nadine

AU - Soyris, Clara

AU - Polla, Daniel L.

AU - Safra, Modi

AU - Zisso, Avia

AU - Powell, Christopher A.

AU - Rebelo-Guiomar, Pedro

AU - Dinges, Nadja

AU - Morin, Violeta

AU - Stock, Michael

AU - Hussain, Mureed

AU - Shahzad, Mohsin

AU - Riazuddin, Saima

AU - Ahmed, Zubair M.

AU - Pfundt, Rolph

AU - Schwarz, Franziska

AU - de Boer, Lonneke

AU - Reis, André

AU - Grozeva, Detilina

AU - Raymond, F. Lucy

AU - Riazuddin, Sheikh

AU - Koolen, David A.

AU - Minczuk, Michal

AU - Roignant, Jean Yves

AU - van Bokhoven, Hans

AU - Schwartz, Schraga

PY - 2018/12/6

Y1 - 2018/12/6

N2 - We describe six persons from three families with three homozygous protein truncating variants in PUS7: c.89_90del (p.Thr30Lysfs∗20), c.1348C>T (p.Arg450∗), and a deletion of the penultimate exon 15. All these individuals have intellectual disability with speech delay, short stature, microcephaly, and aggressive behavior. PUS7 encodes the RNA-independent pseudouridylate synthase 7. Pseudouridylation is the most abundant post-transcriptional modification in RNA, which is primarily thought to stabilize secondary structures of RNA. We show that the disease-related variants lead to abolishment of PUS7 activity on both tRNA and mRNA substrates. Moreover, pus7 knockout in Drosophila melanogaster results in a number of behavioral defects, including increased activity, disorientation, and aggressiveness supporting that neurological defects are caused by PUS7 variants. Our findings demonstrate that RNA pseudouridylation by PUS7 is essential for proper neuronal development and function.

AB - We describe six persons from three families with three homozygous protein truncating variants in PUS7: c.89_90del (p.Thr30Lysfs∗20), c.1348C>T (p.Arg450∗), and a deletion of the penultimate exon 15. All these individuals have intellectual disability with speech delay, short stature, microcephaly, and aggressive behavior. PUS7 encodes the RNA-independent pseudouridylate synthase 7. Pseudouridylation is the most abundant post-transcriptional modification in RNA, which is primarily thought to stabilize secondary structures of RNA. We show that the disease-related variants lead to abolishment of PUS7 activity on both tRNA and mRNA substrates. Moreover, pus7 knockout in Drosophila melanogaster results in a number of behavioral defects, including increased activity, disorientation, and aggressiveness supporting that neurological defects are caused by PUS7 variants. Our findings demonstrate that RNA pseudouridylation by PUS7 is essential for proper neuronal development and function.

KW - Drosophila melanogaster

KW - aggressive behavior

KW - growth delay

KW - intellectual disability

KW - mRNA substrates

KW - microcephaly

KW - neurodevelopmental delay

KW - pseudouridylation

KW - speech delay

KW - tRNA

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AN - SCOPUS:85057190206

SN - 0002-9297

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JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 6

ER -

Variants in PUS7 Cause Intellectual Disability with Speech Delay, Microcephaly, Short Stature, and Aggressive Behavior

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Keywords

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