IQSEC2-Associated Intellectual Disability and Autism
Abstract
1. Introduction
2. Clinical Connection between IQSEC2 and ASD
3. IQSEC2 Structure and Function
4. IQSEC2 and Spine Formation
5. Proteins Implicated in ASD that Interact with IQSEC2
5.1. PSD-95
5.2. IRSp53/BAIAP2, PSD-93, SAP97, CaMKIIa
5.3. Glutamate Receptors
6. Therapeutic Treatment of IQSEC2-Associated ID and Autism
Author Contributions
Funding
Conflicts of Interest
Abbreviations
ID | Intellectual disability |
NMDA | N-methyl-D-aspartate |
PSD | Post synaptic density |
GTP | Guanosine triphosphate |
GDP | Guanosine diphosphate |
ARF | ADP ribosylation factor |
AMPA | α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid |
GABA | Gamma-aminobutyric acid |
ASD | Autism spectrum disorder |
CC | Coiled coil |
PH | Pleckstrin homology |
PRM | Proline rich motif |
PDZ | Post synaptic density protein (PSD95), Drosophila disc large tumor suppressor (Dlg1), and zonula occludens-1 protein (zo-1) |
GEF | Guanine nucleotide exchange factor |
MAGUK | Membrane associated guanylate kinase |
IRSp53 | Insulin receptor substrate of 53 kda |
BAIAP2 | Brain specific angiogenesis inhibitor 1-associated protein 2 |
SAP97 | Synapse associated protein 97 |
CaMKIIa | Calcium calmodulin kinase iia |
GGA3 | Golgi associated gamma adaptin ear containing ARF binding protein 3 |
JNK | C-jun N terminal kinase |
PAM | Positive allosteric modulators |
References
- Shoubridge, C.; Tarpey, P.S.; Abidi, F.; Ramsden, S.L.; Rujirabanjerd, S.; Murphy, J.S.; Boyle, J.; Shaw, M.; Gardner, A.; Proos, A.; et al. Mutations in the guanine nucleotide exchange factor gene IQSEC2 cause non-syndromic intellectual disability. Nat. Genet. 2010, 42, 486–488. [Google Scholar] [CrossRef] [PubMed]
- Mignot, C.; McMahon, A.C.; Bar, C.; Campeau, P.M.; Davidson, C.; Buratti, J.; Nava, C.; Jacquemont, M.L.; Tallot, M.; Milh, M.; et al. IQSEC2-related encephalopathy in males and females: a comparative study including 37 novel patients. Genet. Med. 2019, 4, 837–849. [Google Scholar] [CrossRef] [PubMed]
- Shoubridge, C.; Harvey, R.J.; Dudding-Byth, T. IQSEC2 mutation update and review of the female-specific phenotype spectrum including intellectual disability and epilepsy. Hum. Mutat. 2019, 40, 5–24. [Google Scholar] [CrossRef] [PubMed]
- Sakagami, H.; Sanda, M.; Fukaya, M.; Miyazaki, T.; Sukegawa, J.; Yanagisawa, T.; Suzuki, T.; Fukunaga, K.; Watanabe, M.; Kondo, H. IQ-ArfGEF/BRAG1 is a guanine nucleotide exchange factor for Arf6 that interacts with PSD-95 at postsynaptic density of excitatory synapses. Neurosci. Res. 2008, 60, 199–212. [Google Scholar] [CrossRef] [PubMed]
- Petrovski, S.; Wang, Q.; Erin, L.; Heinzen, E.L.; Allen, A.S.; Goldstein, D.B. Genic Intolerance to Functional Variation and the Interpretation of Personal Genomes. PLoS Genet. 2013, 9, 1–13. [Google Scholar] [CrossRef]
- Kim, Y.; Lee, S.-E.; Park, J.; Kim, M.; Lee, B.; Hwang, D.; Chang, S. ADP-ribosylation Factor 6 (ARF6) Bidirectionally Regulates Dendritic Spine Formation Depending on Neuronal Maturation and Activity. J. Biol. Chem. 2015, 290, 7323–7335. [Google Scholar] [CrossRef]
- Straub, C.; Sabatini, B.L. How to Grow a Synapse. Neuron 2014, 82, 256. [Google Scholar] [CrossRef][Green Version]
- Murphy, J.A.; Jensenb, O.N.; Walikonis, R.S. BRAG1, a Sec7 domain-containing protein, is a component of the postsynaptic density of excitatory synapses. Brain Res. 2006, 1120, 35–45. [Google Scholar] [CrossRef] [PubMed]
- Hinze, S.J.; Jackson, M.R.; Lie, S.; Jolly, L.; Field, M.; Barry, S.C.; Harvey, R.J.; Shoubridge, C. Incorrect dosage of IQSEC2, a known intellectual disability and epilepsy gene, disrupts dendritic spine morphogenesis. Transl. Psychiatry 2017, 7, 1–11. [Google Scholar] [CrossRef] [PubMed]
- Coley, A.A.; Gao, W.-J. PSD95: A synaptic protein implicated in schizophrenia or autism? Prog. Neuro-Psychoph. 2017, 82, 187–194. [Google Scholar] [CrossRef] [PubMed]
- Forrest, M.P.; Euan Parnell, E.; Penzes, P. Dendritic structural plasticity and neuropsychiatric disease. Nat. Rev. Neurosci. 2018, 19, 215–234. [Google Scholar] [CrossRef] [PubMed]
- Frank, R.A.; Komiyama, N.H.; Ryan, T.J.; Zhu, F.; O’Dell, T.J.; Grant, S.G. NMDA receptors are selectively partitioned into complexes and supercomplexes during synapse maturation. Nat. Commun. 2016, 7, 11264. [Google Scholar] [CrossRef] [PubMed]
- Frank, R.A.W.; Zhu, F.; Komiyama, N.H.; Grant, S.G.N. Hierarchical organisation and genetically separable subfamilies of PSD95 postsynaptic supercomplexes. J. Neurochem. 2017, 142, 504–511. [Google Scholar] [CrossRef] [PubMed]
- Brown, J.C.; Petersen, A.; Zhong, L.; Himelright, M.L.; Murphy, J.A.; Walikonis, R.S.; Gerges, N.Z. Bidirectional regulation of synaptic transmission by BRAG1/IQSEC2 and its requirement in long-term depression. Nat. Commun. 2015, 7, 11080. [Google Scholar] [CrossRef] [PubMed]
- Kang, J.; Park, H.; Kim, E. IRSp53/BAIAP2 in dendritic spine development, NMDA receptor regulation, and psychiatric disorders. Neuropharm. 2016, 100, 27–39. [Google Scholar] [CrossRef] [PubMed]
- Rogers, E.J.; Jada, R.; Schragenheim-Rozales, K.; Sah, M.; Cortes, M.; Florence, M.; Levy, N.S.; Moss, R.; Walikonis, R.S.; Palty, R.; et al. An IQSEC2 mutation associated with intellectual disability and autism results in decreased surface AMPA receptors. Front. Mol. Neurosci. 2019, 12, 43. [Google Scholar] [CrossRef]
- Sanda, M.; Kamata, A.; Katsumata, O.; Fukunaga, K.; Watanabe, M.; Kondo, H.; Sakagami, H. The postsynaptic density protein, IQ-ArfGEF/BRAG1, can interact with IRSp53 through its proline-rich sequence. Brain Res. 2009, 1251, 7–15. [Google Scholar] [CrossRef] [PubMed]
- Hell, J.W. CaMKII: Claiming Center Stage in Postsynaptic Function and Organization. Neuron. 2014, 81, 249–265. [Google Scholar] [CrossRef]
- Dosemeci, A.; Makusky, A.J.; Jankowska-Stephens, E.; Yang, X.; Slotta, D.J.; Markey, S.M. Composition of the Synaptic PSD-95 Complex. Mol Cell Proteomics 2007, 6, 1749–1760. [Google Scholar] [CrossRef]
- Guang, S.; Pang, N.; Deng, X.; Yang, L.; He, F.; Wu, L.; Chen, C.; Yin, F.; Peng, J. Synaptopathology Involved in Autism Spectrum Disorder. Front. Cell. Neurosci. 2018, 12, 470. [Google Scholar] [CrossRef]
- Kim, J.-W.; Park, K.; Kang, J.; Gonzales, E.L.T.; Kim, D.G.; Oh, H.A.; Seung, H.; Ko, M.J.; Kwon, K.J.; Kim, K.C.; et al. Pharmacological modulation of AMPA receptor rescues social impairments in animal models of autism. Neuropsychopharmacology 2019, 44, 314–323. [Google Scholar] [CrossRef] [PubMed]
- Myers, K.R.; Wang, G.; Sheng, Y.; Conger, K.K.; Casanova, J.E.; Zhu, J.J. Arf6-BRAG1 regulates JNK-mediated synaptic removal of GluA1-containing AMPA receptors: A new mechanism for nonsyndromic X-linked mental disorder. J. Neurosci. 2012, 32, 11716–11726. [Google Scholar] [CrossRef] [PubMed]
- Elagabani, M.N.; Brisevac, D.; Kintscher, M.; Pohle, J.; Kohr, G.; Schmitz, D.; Kornau, H.-C. Subunit-selective N-Methyl-D-aspartate (NMDA) receptor signaling through brefeldan A-resistant Arf guanine nucleotide exchange factors BRAG1 and BRAG2 during synapse maturation. J. Biol. Chem. 2016, 291, 9105–9118. [Google Scholar] [CrossRef] [PubMed]
- Zerem, A.; Haginoya, K.; Lev, D.; Blumkin, L.; Kivity, S.; Liner, I.; Lerman-Sagie, T. The molecular and phenotypic spectrum of IQSEC2-related epilepsy. Epilepsia 2016, 57, 1858. [Google Scholar] [CrossRef] [PubMed]
- Ahrens-Nicklas, R.C.; Umanah, G.K.; Sondheimer, N.; Deardorff, M.A.; Wilkens, A.B.; Conlin, L.K.; Santani, A.B.; Nesbitt, A.; Juulsola, J.; Ma, E.; et al. Precision therapy for a new disorder of AMPA receptor recycling due to mutations in ATAD1. Neurol. Genet. 2017, 3, e130. [Google Scholar] [CrossRef] [PubMed]
- Piard, J.; Umanah, G.K.E.; Harms, F.L.; Abalde-Atristain, L.; Amram, D.; Chang, M.; Chen, R.; Alawi, M.; Salpietro, V.; Rees, M.I.; et al. A homozygous ATAD1 mutation impairs postsynaptic AMPA receptor trafficking and causes a lethal encephalopathy. Brain 2018, 141, 651–661. [Google Scholar] [CrossRef] [PubMed]
- Umanah, G.K.E.; Pignatelli, M.; Yin, X.; Chen, R.; Crawford, J.; Neifert, S.; Scarffe, L.; Behensky, A.A.; Guiberson, N.; Chang, M.; et al. Thorase variants are associated with defects in glutamatergic neurotransmission that can be rescued by perampanel. Sci. Transl. Med. 2017, 13, 420. [Google Scholar] [CrossRef]
© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Levy, N.S.; Umanah, G.K.E.; Rogers, E.J.; Jada, R.; Lache, O.; Levy, A.P. IQSEC2-Associated Intellectual Disability and Autism. Int. J. Mol. Sci. 2019, 20, 3038. https://doi.org/10.3390/ijms20123038
Levy NS, Umanah GKE, Rogers EJ, Jada R, Lache O, Levy AP. IQSEC2-Associated Intellectual Disability and Autism. International Journal of Molecular Sciences. 2019; 20(12):3038. https://doi.org/10.3390/ijms20123038
Chicago/Turabian StyleLevy, Nina S., George K. E. Umanah, Eli J. Rogers, Reem Jada, Orit Lache, and Andrew P. Levy. 2019. "IQSEC2-Associated Intellectual Disability and Autism" International Journal of Molecular Sciences 20, no. 12: 3038. https://doi.org/10.3390/ijms20123038
APA StyleLevy, N. S., Umanah, G. K. E., Rogers, E. J., Jada, R., Lache, O., & Levy, A. P. (2019). IQSEC2-Associated Intellectual Disability and Autism. International Journal of Molecular Sciences, 20(12), 3038. https://doi.org/10.3390/ijms20123038