PMID- 30443311
OWN - NLM
STAT- MEDLINE
DCOM- 20181221
LR  - 20181221
IS  - 2040-2392 (Electronic)
VI  - 9
DP  - 2018
TI  - Loss of the Chr16p11.2 ASD candidate gene QPRT leads to aberrant neuronal 
      differentiation in the SH-SY5Y neuronal cell model.
PG  - 56
LID - 10.1186/s13229-018-0239-z [doi]
LID - 56
AB  - BACKGROUND: Altered neuronal development is discussed as the underlying 
      pathogenic mechanism of autism spectrum disorders (ASD). Copy number variations 
      of 16p11.2 have recurrently been identified in individuals with ASD. Of the 29 
      genes within this region, quinolinate phosphoribosyltransferase (QPRT) showed the 
      strongest regulation during neuronal differentiation of SH-SY5Y neuroblastoma 
      cells. We hypothesized a causal relation between this tryptophan 
      metabolism-related enzyme and neuronal differentiation. We thus analyzed the 
      effect of QPRT on the differentiation of SH-SY5Y and specifically focused on 
      neuronal morphology, metabolites of the tryptophan pathway, and the 
      neurodevelopmental transcriptome. METHODS: The gene dosage-dependent change of 
      QPRT expression following Chr16p11.2 deletion was investigated in a 
      lymphoblastoid cell line (LCL) of a deletion carrier and compared to his 
      non-carrier parents. Expression of QPRT was tested for correlation with 
      neuromorphology in SH-SY5Y cells. QPRT function was inhibited in SH-SY5Y 
      neuroblastoma cells using (i) siRNA knockdown (KD), (ii) chemical mimicking of 
      loss of QPRT, and (iii) complete CRISPR/Cas9-mediated knock out (KO). QPRT-KD 
      cells underwent morphological analysis. Chemically inhibited and QPRT-KO cells 
      were characterized using viability assays. Additionally, QPRT-KO cells underwent 
      metabolite and whole transcriptome analyses. Genes differentially expressed upon 
      KO of QPRT were tested for enrichment in biological processes and co-regulated 
      gene-networks of the human brain. RESULTS: QPRT expression was reduced in the LCL 
      of the deletion carrier and significantly correlated with the neuritic complexity 
      of SH-SY5Y. The reduction of QPRT altered neuronal morphology of differentiated 
      SH-SY5Y cells. Chemical inhibition as well as complete KO of the gene were lethal 
      upon induction of neuronal differentiation, but not proliferation. The 
      QPRT-associated tryptophan pathway was not affected by KO. At the transcriptome 
      level, genes linked to neurodevelopmental processes and synaptic structures were 
      affected. Differentially regulated genes were enriched for ASD candidates, and 
      co-regulated gene networks were implicated in the development of the dorsolateral 
      prefrontal cortex, the hippocampus, and the amygdala. CONCLUSIONS: In this study, 
      QPRT was causally related to in vitro neuronal differentiation of SH-SY5Y cells 
      and affected the regulation of genes and gene networks previously implicated in 
      ASD. Thus, our data suggest that QPRT may play an important role in the 
      pathogenesis of ASD in Chr16p11.2 deletion carriers.
FAU - Haslinger, Denise
AU  - Haslinger D
AD  - 1Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, 
      University Hospital Frankfurt, JW Goethe University Frankfurt, Frankfurt am Main, 
      Germany.
FAU - Waltes, Regina
AU  - Waltes R
AD  - 1Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, 
      University Hospital Frankfurt, JW Goethe University Frankfurt, Frankfurt am Main, 
      Germany.
FAU - Yousaf, Afsheen
AU  - Yousaf A
AD  - 1Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, 
      University Hospital Frankfurt, JW Goethe University Frankfurt, Frankfurt am Main, 
      Germany.
FAU - Lindlar, Silvia
AU  - Lindlar S
AD  - 1Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, 
      University Hospital Frankfurt, JW Goethe University Frankfurt, Frankfurt am Main, 
      Germany.
FAU - Schneider, Ines
AU  - Schneider I
AD  - Institute of Experimental Cancer Research in Pediatrics, Frankfurt am Main, 
      Germany.
FAU - Lim, Chai K
AU  - Lim CK
AD  - 3Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South 
      Wales Australia.
FAU - Tsai, Meng-Miao
AU  - Tsai MM
AD  - 4Neuropathology, University of Giessen, Giessen, Germany.
FAU - Garvalov, Boyan K
AU  - Garvalov BK
AD  - 4Neuropathology, University of Giessen, Giessen, Germany.
AD  - 5Department of Microvascular Biology and Pathobiology, European Center for 
      Angioscience (ECAS), Medical Faculty Mannheim, University of Heidelberg, 
      Heidelberg, Germany.
FAU - Acker-Palmer, Amparo
AU  - Acker-Palmer A
AD  - 6Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular 
      Life Sciences (BMLS), JW Goethe University of Frankfurt, Frankfurt am Main, 
      Germany.
FAU - Krezdorn, Nicolas
AU  - Krezdorn N
AD  - 7GenXPro GmbH, Frankfurt am Main, Germany.
FAU - Rotter, Bjorn
AU  - Rotter B
AD  - 7GenXPro GmbH, Frankfurt am Main, Germany.
FAU - Acker, Till
AU  - Acker T
AD  - 4Neuropathology, University of Giessen, Giessen, Germany.
FAU - Guillemin, Gilles J
AU  - Guillemin GJ
AD  - 3Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South 
      Wales Australia.
FAU - Fulda, Simone
AU  - Fulda S
AD  - Institute of Experimental Cancer Research in Pediatrics, Frankfurt am Main, 
      Germany.
FAU - Freitag, Christine M
AU  - Freitag CM
AD  - 1Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, 
      University Hospital Frankfurt, JW Goethe University Frankfurt, Frankfurt am Main, 
      Germany.
FAU - Chiocchetti, Andreas G
AU  - Chiocchetti AG
AUID- ORCID: 0000-0002-7329-9985
AD  - 1Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, 
      University Hospital Frankfurt, JW Goethe University Frankfurt, Frankfurt am Main, 
      Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20181106
PL  - England
TA  - Mol Autism
JT  - Molecular autism
JID - 101534222
RN  - EC 2.4.2.- (Pentosyltransferases)
RN  - EC 2.4.2.19 (nicotinate-nucleotide diphosphorylase (carboxylating))
SB  - IM
MH  - Autism Spectrum Disorder/*genetics
MH  - Cell Differentiation/*genetics
MH  - Cell Line, Tumor
MH  - Chromosome Deletion
MH  - Chromosomes, Human, Pair 16
MH  - DNA Copy Number Variations
MH  - Humans
MH  - Neurons/*cytology
MH  - Pentosyltransferases/*genetics
PMC - PMC6220561
OTO - NOTNLM
OT  - 16p11.2
OT  - Autism
OT  - CRISPR/Cas9
OT  - Kynurenine
OT  - Quinolinate phosphoribosyltransferase
OT  - Quinolinic acid
OT  - Sholl analysis
COIS- All study participants have given written informed consent, and the genetic study 
      has been positively reviewed by the ethic's committee Frankfurt (No 267/09).All 
      authors agree to publish the presented work.All authors declare that they have no 
      competing interests.Springer Nature remains neutral with regard to jurisdictional 
      claims in published maps and institutional affiliations.
EDAT- 2018/11/18 06:00
MHDA- 2018/12/24 06:00
PMCR- 2018/11/06
CRDT- 2018/11/17 06:00
PHST- 2018/05/02 00:00 [received]
PHST- 2018/10/15 00:00 [accepted]
PHST- 2018/11/17 06:00 [entrez]
PHST- 2018/11/18 06:00 [pubmed]
PHST- 2018/12/24 06:00 [medline]
PHST- 2018/11/06 00:00 [pmc-release]
AID - 239 [pii]
AID - 10.1186/s13229-018-0239-z [doi]
PST - epublish
SO  - Mol Autism. 2018 Nov 6;9:56. doi: 10.1186/s13229-018-0239-z. eCollection 2018.