Variation in a range of mTOR-related genes associates with intracranial volume and intellectual disability

M. R.F. Reijnders; M. Kousi; G. M. Van Woerden; M. Klein; J. Bralten; G. M.S. Mancini; T. Van Essen; M. Proietti-Onori; E. E.J. Smeets; M. Van Gastel; A. P.A. Stegmann; S. J.C. Stevens; S. H. Lelieveld; C. Gilissen; R. Pfundt; P. L. Tan; T. Kleefstra; B. Franke; Y. Elgersma; Elias Nicholas Katsanis; H. G. Brunner

doi:10.1038/s41467-017-00933-6

Variation in a range of mTOR-related genes associates with intracranial volume and intellectual disability

M. R.F. Reijnders, M. Kousi, G. M. Van Woerden, M. Klein, J. Bralten, G. M.S. Mancini, T. Van Essen, M. Proietti-Onori, E. E.J. Smeets, M. Van Gastel, A. P.A. Stegmann, S. J.C. Stevens, S. H. Lelieveld, C. Gilissen, R. Pfundt, P. L. Tan, T. Kleefstra, B. Franke, Y. Elgersma, Elias Nicholas KatsanisH. G. Brunner^*

^*Corresponding author for this work

Pediatrics

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Abstract

De novo mutations in specific mTOR pathway genes cause brain overgrowth in the context of intellectual disability (ID). By analyzing 101 mMTOR-related genes in a large ID patient cohort and two independent population cohorts, we show that these genes modulate brain growth in health and disease. We report the mTOR activator gene RHEB as an ID gene that is associated with megalencephaly when mutated. Functional testing of mutant RHEB in vertebrate animal models indicates pathway hyperactivation with a concomitant increase in cell and head size, aberrant neuronal migration, and induction of seizures, concordant with the human phenotype. This study reveals that tight control of brain volume is exerted through a large community of mTOR-related genes. Human brain volume can be altered, by either rare disruptive events causing hyperactivation of the pathway, or through the collective effects of common alleles.

Original language	English (US)
Article number	1052
Journal	Nature communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-00933-6
State	Published - Dec 1 2017

ASJC Scopus subject areas

Physics and Astronomy(all)
Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)

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10.1038/s41467-017-00933-6

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Reijnders, M. R. F., Kousi, M., Van Woerden, G. M., Klein, M., Bralten, J., Mancini, G. M. S., Van Essen, T., Proietti-Onori, M., Smeets, E. E. J., Van Gastel, M., Stegmann, A. P. A., Stevens, S. J. C., Lelieveld, S. H., Gilissen, C., Pfundt, R., Tan, P. L., Kleefstra, T., Franke, B., Elgersma, Y., ... Brunner, H. G. (2017). Variation in a range of mTOR-related genes associates with intracranial volume and intellectual disability. Nature communications, 8(1), Article 1052. https://doi.org/10.1038/s41467-017-00933-6

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title = "Variation in a range of mTOR-related genes associates with intracranial volume and intellectual disability",

abstract = "De novo mutations in specific mTOR pathway genes cause brain overgrowth in the context of intellectual disability (ID). By analyzing 101 mMTOR-related genes in a large ID patient cohort and two independent population cohorts, we show that these genes modulate brain growth in health and disease. We report the mTOR activator gene RHEB as an ID gene that is associated with megalencephaly when mutated. Functional testing of mutant RHEB in vertebrate animal models indicates pathway hyperactivation with a concomitant increase in cell and head size, aberrant neuronal migration, and induction of seizures, concordant with the human phenotype. This study reveals that tight control of brain volume is exerted through a large community of mTOR-related genes. Human brain volume can be altered, by either rare disruptive events causing hyperactivation of the pathway, or through the collective effects of common alleles.",

author = "Reijnders, {M. R.F.} and M. Kousi and {Van Woerden}, {G. M.} and M. Klein and J. Bralten and Mancini, {G. M.S.} and {Van Essen}, T. and M. Proietti-Onori and Smeets, {E. E.J.} and {Van Gastel}, M. and Stegmann, {A. P.A.} and Stevens, {S. J.C.} and Lelieveld, {S. H.} and C. Gilissen and R. Pfundt and Tan, {P. L.} and T. Kleefstra and B. Franke and Y. Elgersma and Katsanis, {Elias Nicholas} and Brunner, {H. G.}",

note = "Funding Information: We thank the participating families. We thank all clinicians involved for referring individuals with ID for diagnostic exome sequencing. We thank Hanka Venselaar for interpretation of identified mutations. We thank Francesca Wiersma for technical assistance. The ENIGMA Consortium provided summary statistics of the consortium findings to this project. The original publication of those findings as well as the list of contributing samples and people can be found on the ENIGMA website: http://enigma.ini.usc.edu/. The Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium also contributed with an independent set of summary statistics of consortium findings. The contributing cohorts and persons can be found on previous publications of the CHARGE consortium as listed on the website: http://www.chargeconsortium.com/. Part of this work was carried out on the Dutch national e-infrastructure with the support of SURF Foundation. Barbara Franke is supported by funding from a personal Vici grant of the Netherlands Organisation for Scientific Research (NWO; grant 016-130-669), from the European Community{\textquoteright}s Seventh Framework Programme (FP7/2007–2013) under grant agreements no. 602805 (Aggressotype) and no. 602450 (IMAGEMEND), and from the European Community{\textquoteright}s Horizon 2020 Programme (H2020/2014–2020) under grant agreement no. 643051 (MiND). In addition, her work is supported by a grant for the ENIGMA Consortium (grant number U54 EB020403) from the BD2K Initiative of a cross-NIH partnership. Publisher Copyright: {\textcopyright} 2017 The Author(s).",

year = "2017",

month = dec,

day = "1",

doi = "10.1038/s41467-017-00933-6",

language = "English (US)",

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Reijnders, MRF, Kousi, M, Van Woerden, GM, Klein, M, Bralten, J, Mancini, GMS, Van Essen, T, Proietti-Onori, M, Smeets, EEJ, Van Gastel, M, Stegmann, APA, Stevens, SJC, Lelieveld, SH, Gilissen, C, Pfundt, R, Tan, PL, Kleefstra, T, Franke, B, Elgersma, Y, Katsanis, EN & Brunner, HG 2017, 'Variation in a range of mTOR-related genes associates with intracranial volume and intellectual disability', Nature communications, vol. 8, no. 1, 1052. https://doi.org/10.1038/s41467-017-00933-6

TY - JOUR

T1 - Variation in a range of mTOR-related genes associates with intracranial volume and intellectual disability

AU - Reijnders, M. R.F.

AU - Kousi, M.

AU - Van Woerden, G. M.

AU - Klein, M.

AU - Bralten, J.

AU - Mancini, G. M.S.

AU - Van Essen, T.

AU - Proietti-Onori, M.

AU - Smeets, E. E.J.

AU - Van Gastel, M.

AU - Stegmann, A. P.A.

AU - Stevens, S. J.C.

AU - Lelieveld, S. H.

AU - Gilissen, C.

AU - Pfundt, R.

AU - Tan, P. L.

AU - Kleefstra, T.

AU - Franke, B.

AU - Elgersma, Y.

AU - Katsanis, Elias Nicholas

AU - Brunner, H. G.

N1 - Funding Information: We thank the participating families. We thank all clinicians involved for referring individuals with ID for diagnostic exome sequencing. We thank Hanka Venselaar for interpretation of identified mutations. We thank Francesca Wiersma for technical assistance. The ENIGMA Consortium provided summary statistics of the consortium findings to this project. The original publication of those findings as well as the list of contributing samples and people can be found on the ENIGMA website: http://enigma.ini.usc.edu/. The Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium also contributed with an independent set of summary statistics of consortium findings. The contributing cohorts and persons can be found on previous publications of the CHARGE consortium as listed on the website: http://www.chargeconsortium.com/. Part of this work was carried out on the Dutch national e-infrastructure with the support of SURF Foundation. Barbara Franke is supported by funding from a personal Vici grant of the Netherlands Organisation for Scientific Research (NWO; grant 016-130-669), from the European Community’s Seventh Framework Programme (FP7/2007–2013) under grant agreements no. 602805 (Aggressotype) and no. 602450 (IMAGEMEND), and from the European Community’s Horizon 2020 Programme (H2020/2014–2020) under grant agreement no. 643051 (MiND). In addition, her work is supported by a grant for the ENIGMA Consortium (grant number U54 EB020403) from the BD2K Initiative of a cross-NIH partnership. Publisher Copyright: © 2017 The Author(s).

PY - 2017/12/1

Y1 - 2017/12/1

N2 - De novo mutations in specific mTOR pathway genes cause brain overgrowth in the context of intellectual disability (ID). By analyzing 101 mMTOR-related genes in a large ID patient cohort and two independent population cohorts, we show that these genes modulate brain growth in health and disease. We report the mTOR activator gene RHEB as an ID gene that is associated with megalencephaly when mutated. Functional testing of mutant RHEB in vertebrate animal models indicates pathway hyperactivation with a concomitant increase in cell and head size, aberrant neuronal migration, and induction of seizures, concordant with the human phenotype. This study reveals that tight control of brain volume is exerted through a large community of mTOR-related genes. Human brain volume can be altered, by either rare disruptive events causing hyperactivation of the pathway, or through the collective effects of common alleles.

AB - De novo mutations in specific mTOR pathway genes cause brain overgrowth in the context of intellectual disability (ID). By analyzing 101 mMTOR-related genes in a large ID patient cohort and two independent population cohorts, we show that these genes modulate brain growth in health and disease. We report the mTOR activator gene RHEB as an ID gene that is associated with megalencephaly when mutated. Functional testing of mutant RHEB in vertebrate animal models indicates pathway hyperactivation with a concomitant increase in cell and head size, aberrant neuronal migration, and induction of seizures, concordant with the human phenotype. This study reveals that tight control of brain volume is exerted through a large community of mTOR-related genes. Human brain volume can be altered, by either rare disruptive events causing hyperactivation of the pathway, or through the collective effects of common alleles.

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SN - 2041-1723

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JO - Nature communications

JF - Nature communications

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Variation in a range of mTOR-related genes associates with intracranial volume and intellectual disability

Abstract

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