Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures

Leila K. Myrick, Pan Yue Deng, Hideharu Hashimoto, Young Mi Oh, Yongcheol Cho, Mickael J. Poidevin, Joshua A. Suhl, Jeannie Visootsak, Valeria Cavalli, Peng Jin, Xiaodong Cheng, Stephen T. Warren, Vitaly A. Klyachko

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

Fragile X syndrome (FXS) results in intellectual disability (ID) most often caused by silencing of the fragile X mental retardation 1 (FMR1) gene. The resulting absence of fragile X mental retardation protein 1 (FMRP) leads to both pre- and postsynaptic defects, yet whether the pre- and postsynaptic functions of FMRP are independent and have distinct roles in FXS neuropathology remain poorly understood. Here, we demonstrate an independent presynaptic function for FMRP through the study of an ID patient with an FMR1 missense mutation. This mutation, c.413G > A (R138Q), preserves FMRP's canonical functions in RNA binding and translational regulation, which are traditionally associated with postsynaptic compartments. However, neuronally driven expression of the mutant FMRP is unable to rescue structural defects at the neuromuscular junction in fragile x mental retardation 1 (dfmr1)-deficient Drosophila, suggesting a presynaptic-specific impairment. Furthermore, mutant FMRP loses the ability to rescue presynaptic action potential (AP) broadening in Fmr1 KO mice. The R138Q mutation also disrupts FMRP's interactionwith the large-conductance calciumactivated potassium (BK) channels that modulate AP width. These results reveal a presynaptic- and translation-independent function of FMRP that is linked to a specific subset of FXS phenotypes.

Original languageEnglish
Pages (from-to)949-956
Number of pages8
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number4
DOIs
Publication statusPublished - 2015 Jan 27
Externally publishedYes

Fingerprint

Fragile X Mental Retardation Protein
Missense Mutation
Intellectual Disability
Seizures
Fragile X Syndrome
Mutant Proteins
Action Potentials
Large-Conductance Calcium-Activated Potassium Channels
Mutation
Aptitude
Neuromuscular Junction
Potassium Channels
Drosophila
RNA
Phenotype

Keywords

  • Bk channels
  • Fmr1 sequencing
  • FMRP
  • Fragile X syndrome
  • Missense mutation

ASJC Scopus subject areas

  • General

Cite this

Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures. / Myrick, Leila K.; Deng, Pan Yue; Hashimoto, Hideharu; Oh, Young Mi; Cho, Yongcheol; Poidevin, Mickael J.; Suhl, Joshua A.; Visootsak, Jeannie; Cavalli, Valeria; Jin, Peng; Cheng, Xiaodong; Warren, Stephen T.; Klyachko, Vitaly A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 4, 27.01.2015, p. 949-956.

Research output: Contribution to journalArticle

Myrick, LK, Deng, PY, Hashimoto, H, Oh, YM, Cho, Y, Poidevin, MJ, Suhl, JA, Visootsak, J, Cavalli, V, Jin, P, Cheng, X, Warren, ST & Klyachko, VA 2015, 'Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures', Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 4, pp. 949-956. https://doi.org/10.1073/pnas.1423094112
Myrick, Leila K. ; Deng, Pan Yue ; Hashimoto, Hideharu ; Oh, Young Mi ; Cho, Yongcheol ; Poidevin, Mickael J. ; Suhl, Joshua A. ; Visootsak, Jeannie ; Cavalli, Valeria ; Jin, Peng ; Cheng, Xiaodong ; Warren, Stephen T. ; Klyachko, Vitaly A. / Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures. In: Proceedings of the National Academy of Sciences of the United States of America. 2015 ; Vol. 112, No. 4. pp. 949-956.
@article{6f4a3e99b6e24619a900a4c4a99c10ac,
title = "Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures",
abstract = "Fragile X syndrome (FXS) results in intellectual disability (ID) most often caused by silencing of the fragile X mental retardation 1 (FMR1) gene. The resulting absence of fragile X mental retardation protein 1 (FMRP) leads to both pre- and postsynaptic defects, yet whether the pre- and postsynaptic functions of FMRP are independent and have distinct roles in FXS neuropathology remain poorly understood. Here, we demonstrate an independent presynaptic function for FMRP through the study of an ID patient with an FMR1 missense mutation. This mutation, c.413G > A (R138Q), preserves FMRP's canonical functions in RNA binding and translational regulation, which are traditionally associated with postsynaptic compartments. However, neuronally driven expression of the mutant FMRP is unable to rescue structural defects at the neuromuscular junction in fragile x mental retardation 1 (dfmr1)-deficient Drosophila, suggesting a presynaptic-specific impairment. Furthermore, mutant FMRP loses the ability to rescue presynaptic action potential (AP) broadening in Fmr1 KO mice. The R138Q mutation also disrupts FMRP's interactionwith the large-conductance calciumactivated potassium (BK) channels that modulate AP width. These results reveal a presynaptic- and translation-independent function of FMRP that is linked to a specific subset of FXS phenotypes.",
keywords = "Bk channels, Fmr1 sequencing, FMRP, Fragile X syndrome, Missense mutation",
author = "Myrick, {Leila K.} and Deng, {Pan Yue} and Hideharu Hashimoto and Oh, {Young Mi} and Yongcheol Cho and Poidevin, {Mickael J.} and Suhl, {Joshua A.} and Jeannie Visootsak and Valeria Cavalli and Peng Jin and Xiaodong Cheng and Warren, {Stephen T.} and Klyachko, {Vitaly A.}",
year = "2015",
month = "1",
day = "27",
doi = "10.1073/pnas.1423094112",
language = "English",
volume = "112",
pages = "949--956",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "4",

}

TY - JOUR

T1 - Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures

AU - Myrick, Leila K.

AU - Deng, Pan Yue

AU - Hashimoto, Hideharu

AU - Oh, Young Mi

AU - Cho, Yongcheol

AU - Poidevin, Mickael J.

AU - Suhl, Joshua A.

AU - Visootsak, Jeannie

AU - Cavalli, Valeria

AU - Jin, Peng

AU - Cheng, Xiaodong

AU - Warren, Stephen T.

AU - Klyachko, Vitaly A.

PY - 2015/1/27

Y1 - 2015/1/27

N2 - Fragile X syndrome (FXS) results in intellectual disability (ID) most often caused by silencing of the fragile X mental retardation 1 (FMR1) gene. The resulting absence of fragile X mental retardation protein 1 (FMRP) leads to both pre- and postsynaptic defects, yet whether the pre- and postsynaptic functions of FMRP are independent and have distinct roles in FXS neuropathology remain poorly understood. Here, we demonstrate an independent presynaptic function for FMRP through the study of an ID patient with an FMR1 missense mutation. This mutation, c.413G > A (R138Q), preserves FMRP's canonical functions in RNA binding and translational regulation, which are traditionally associated with postsynaptic compartments. However, neuronally driven expression of the mutant FMRP is unable to rescue structural defects at the neuromuscular junction in fragile x mental retardation 1 (dfmr1)-deficient Drosophila, suggesting a presynaptic-specific impairment. Furthermore, mutant FMRP loses the ability to rescue presynaptic action potential (AP) broadening in Fmr1 KO mice. The R138Q mutation also disrupts FMRP's interactionwith the large-conductance calciumactivated potassium (BK) channels that modulate AP width. These results reveal a presynaptic- and translation-independent function of FMRP that is linked to a specific subset of FXS phenotypes.

AB - Fragile X syndrome (FXS) results in intellectual disability (ID) most often caused by silencing of the fragile X mental retardation 1 (FMR1) gene. The resulting absence of fragile X mental retardation protein 1 (FMRP) leads to both pre- and postsynaptic defects, yet whether the pre- and postsynaptic functions of FMRP are independent and have distinct roles in FXS neuropathology remain poorly understood. Here, we demonstrate an independent presynaptic function for FMRP through the study of an ID patient with an FMR1 missense mutation. This mutation, c.413G > A (R138Q), preserves FMRP's canonical functions in RNA binding and translational regulation, which are traditionally associated with postsynaptic compartments. However, neuronally driven expression of the mutant FMRP is unable to rescue structural defects at the neuromuscular junction in fragile x mental retardation 1 (dfmr1)-deficient Drosophila, suggesting a presynaptic-specific impairment. Furthermore, mutant FMRP loses the ability to rescue presynaptic action potential (AP) broadening in Fmr1 KO mice. The R138Q mutation also disrupts FMRP's interactionwith the large-conductance calciumactivated potassium (BK) channels that modulate AP width. These results reveal a presynaptic- and translation-independent function of FMRP that is linked to a specific subset of FXS phenotypes.

KW - Bk channels

KW - Fmr1 sequencing

KW - FMRP

KW - Fragile X syndrome

KW - Missense mutation

UR - http://www.scopus.com/inward/record.url?scp=84921811954&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84921811954&partnerID=8YFLogxK

U2 - 10.1073/pnas.1423094112

DO - 10.1073/pnas.1423094112

M3 - Article

VL - 112

SP - 949

EP - 956

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 4

ER -