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; N. 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, N. KatsanisH. G. Brunner^*

^*Corresponding author for this work

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

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
Article number	1052
Number of pages	12
Journal	Nature Communications
Volume	8
DOIs	https://doi.org/10.1038/s41467-017-00933-6
Publication status	Published - 20 Oct 2017

Keywords

TUBEROUS SCLEROSIS COMPLEX
MESSENGER-RNA TRANSLATION
IN-VIVO
INTRACTABLE EPILEPSY
CORTICAL DEVELOPMENT
MIGRATION DEFICITS
SOMATIC MUTATIONS
MAMMALIAN TARGET
CEREBRAL-CORTEX
SET ANALYSIS

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Cite this

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, 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.",

keywords = "TUBEROUS SCLEROSIS COMPLEX, MESSENGER-RNA TRANSLATION, IN-VIVO, INTRACTABLE EPILEPSY, CORTICAL DEVELOPMENT, MIGRATION DEFICITS, SOMATIC MUTATIONS, MAMMALIAN TARGET, CEREBRAL-CORTEX, SET ANALYSIS",

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 N. Katsanis and Brunner, {H. G.}",

year = "2017",

month = oct,

day = "20",

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

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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, N & Brunner, HG 2017, 'Variation in a range of mTOR-related genes associates with intracranial volume and intellectual disability', Nature Communications, vol. 8, 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, N.

AU - Brunner, H. G.

PY - 2017/10/20

Y1 - 2017/10/20

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.

KW - TUBEROUS SCLEROSIS COMPLEX

KW - MESSENGER-RNA TRANSLATION

KW - IN-VIVO

KW - INTRACTABLE EPILEPSY

KW - CORTICAL DEVELOPMENT

KW - MIGRATION DEFICITS

KW - SOMATIC MUTATIONS

KW - MAMMALIAN TARGET

KW - CEREBRAL-CORTEX

KW - SET ANALYSIS

U2 - 10.1038/s41467-017-00933-6

DO - 10.1038/s41467-017-00933-6

M3 - Article

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

M1 - 1052

ER -