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Cancer Cell death Cell cycle Cytoskeleton Exo/endocytosis Differentiation Division Organelles Signalling Stem cells Trafficking
Cell Biology International (2010) 34, 13–19 (Printed in Great Britain)
Review article
Genetic factors and epigenetic factors for autism: endoplasmic reticulum stress and impaired synaptic function
Takashi Momoi*1, Eriko Fujita*, Haruki Senoo† and Mariko Momoi‡
*Division of Development and Differentiation, National Institute of Neuroscience, 4-1-1 Ogawahigashi-machi, Kodaira, Tokyo 187-8502, Japan, †Department of Cell Biology and Morphology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita City, Akita 010-8543, Japan, and ‡Department of Paediatrics, Jichi Medical University, 3311-1 Yakushiji, Shimotsukeshi, Tochigi 329-0498, Japan


The molecular pathogenesis of ASD (autism spectrum disorder), one of the heritable neurodevelopmental disorders, is not well understood, although over 15 autistic-susceptible gene loci have been extensively studied. A major issue is whether the proteins that these candidate genes encode are involved in general function and signal transduction. Several mutations in genes encoding synaptic adhesion molecules such as neuroligin, neurexin, CNTNAP (contactin-associated protein) and CADM1 (cell-adhesion molecule 1) found in ASD suggest that impaired synaptic function is the underlying pathogenesis. However, knockout mouse models of these mutations do not show all of the autism-related symptoms, suggesting that gain-of-function in addition to loss-of-function arising from these mutations may be associated with ASD pathogenesis. Another finding is that family members with a given mutation frequently do not manifest autistic symptoms, which possibly may be because of gender effects, dominance theory and environmental factors, including hormones and stress. Thus epigenetic factors complicate our understanding of the relationship between these mutated genes and ASD pathogenesis. We focus in the present review on findings that ER (endoplasmic reticulum) stress arising from these mutations causes a trafficking disorder of synaptic receptors, such as GABA (γ-aminobutyric acid) B-receptors, and leads to their impaired synaptic function and signal transduction. In the present review we propose a hypothesis that ASD pathogenesis is linked not only to loss-of-function but also to gain-of-function, with an ER stress response to unfolded proteins under the influence of epigenetic factors.


Key words: autism, cell-adhesion molecule, endoplasmic reticulum stress, synapse, neuroligin

Abbreviations: ASD, autism spectrum disorder, ATF, activating transcription factor, AUTS, autism susceptibility, CADM1, cell-adhesion molecule 1, CHOP, C/EBP (CAAT/enhancer binding protein) homologous protein, CNTNAP2, contactin associated protein-2, CREB, cAMP response-element-binding protein, eIF2α, eukaryotic initiation factor 2α, ER, endoplasmic reticulum, ERAD, ER-associated degradation, GABA, γ-aminobutyric acid, JNK, c-Jun N-terminal kinase, KI, knockin, KO, knockout, MECP2, methyl-CpG-binding protein 2, MR, mental retardation, NLGN, neuroligin, Nrx, neurexin, PDD, pervasive developmental disorder, PERK, PKR (protein kinase regulated by RNA)-like ER kinase, PSD, postsynaptic density, SNP, single nucleotide polymorphism, UPR, unfolded protein response, USV, ultrasonic vocalization

1To whom correspondence should be addressed (email momoi@ncnp.go.jp).


Received 30 September 2009/29 October 2009; accepted 4 November 2009

Published online 16 December 2009, doi:10.1042/CBI20090250


© 2010 The Author(s) Journal compilation. © 2010 Portland Press Ltd


ISSN Print: 1065-6995
ISSN Electronic: 1095-8355
Published by Portland Press Limited on behalf of the International Federation for Cell Biology (IFCB)