Altered neurite morphology and cholinergic function of induced pluripotent stem cell-derived neurons from a patient with Kleefstra syndrome and autism

The aim of the present study was to establish an in vitro Kleefstra syndrome (KS) disease model using the human induced pluripotent stem cell (hiPSC) technology. Previously, an autism spectrum disorder (ASD) patient with Kleefstra syndrome (KS-ASD) carrying a deleterious premature termination codon...

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Bibliographic Details
Published in:	Translational psychiatry Vol. 7; no. 7; p. e1179
Main Authors:	Nagy, J, Kobolák, J, Berzsenyi, S, Ábrahám, Z, Avci, H X, Bock, I, Bekes, Z, Hodoscsek, B, Chandrasekaran, A, Téglási, A, Dezső, P, Koványi, B, Vörös, E T, Fodor, L, Szél, T, Németh, K, Balázs, A, Dinnyés, A, Lendvai, B, Lévay, G, Román, V
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 25-07-2017 Nature Publishing Group
Subjects:	13/100 13/106 14/34 14/63 38/77 631/378/340 631/532 Acetylcholine - administration & dosage Acetylcholine - physiology Autism Autism Spectrum Disorder - complications Autism Spectrum Disorder - genetics Autism Spectrum Disorder - pathology Autism Spectrum Disorder - physiopathology Behavioral Sciences Biological Psychology Calcium Signaling Cell Differentiation Cells, Cultured Child Chromosome Deletion Chromosomes, Human, Pair 9 - genetics Craniofacial Abnormalities - complications Craniofacial Abnormalities - genetics Craniofacial Abnormalities - pathology Craniofacial Abnormalities - physiopathology Female Gene Expression Heart Defects, Congenital - complications Heart Defects, Congenital - genetics Heart Defects, Congenital - pathology Heart Defects, Congenital - physiopathology Histone-Lysine N-Methyltransferase - genetics Humans Intellectual Disability - complications Intellectual Disability - genetics Intellectual Disability - pathology Intellectual Disability - physiopathology Male Medicine Medicine & Public Health Models, Neurological Morphology Mutation Neural Stem Cells - physiology Neurites - pathology Neurodevelopmental disorders Neurosciences Original original-article Pharmacotherapy Pluripotent Stem Cells - physiology Psychiatry RNA, Messenger - metabolism Stem cells
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Summary:	The aim of the present study was to establish an in vitro Kleefstra syndrome (KS) disease model using the human induced pluripotent stem cell (hiPSC) technology. Previously, an autism spectrum disorder (ASD) patient with Kleefstra syndrome (KS-ASD) carrying a deleterious premature termination codon mutation in the EHMT1 gene was identified. Patient specific hiPSCs generated from peripheral blood mononuclear cells of the KS-ASD patient were differentiated into post-mitotic cortical neurons. Lower levels of EHMT1 mRNA as well as protein expression were confirmed in these cells. Morphological analysis on neuronal cells differentiated from the KS-ASD patient-derived hiPSC clones showed significantly shorter neurites and reduced arborization compared to cells generated from healthy controls. Moreover, density of dendritic protrusions of neuronal cells derived from KS-ASD hiPSCs was lower than that of control cells. Synaptic connections and spontaneous neuronal activity measured by live cell calcium imaging could be detected after 5 weeks of differentiation, when KS-ASD cells exhibited higher sensitivity of calcium responses to acetylcholine stimulation indicating a lower nicotinic cholinergic tone at baseline condition in KS-ASD cells. In addition, gene expression profiling of differentiated neuronal cells from the KS-ASD patient revealed higher expression of proliferation-related genes and lower mRNA levels of genes involved in neuronal maturation and migration. Our data demonstrate anomalous neuronal morphology, functional activity and gene expression in KS-ASD patient-specific hiPSC-derived neuronal cultures, which offers an in vitro system that contributes to a better understanding of KS and potentially other neurodevelopmental disorders including ASD.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Current address: Universitaets-Hals-Nasen-Ohren-Klinik, Tuebingen, Germany. These authors contributed equally to this work.
ISSN:	2158-3188 2158-3188
DOI:	10.1038/tp.2017.144