PMID- 35094084
OWN - NLM
STAT- MEDLINE
DCOM- 20220608
LR  - 20240216
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 31
IP  - 11
DP  - 2022 Jun 4
TI  - Deregulation of microtubule organization and RNA metabolism in Arx models for 
      lissencephaly and developmental epileptic encephalopathy.
PG  - 1884-1908
LID - 10.1093/hmg/ddac028 [doi]
AB  - X-linked lissencephaly with abnormal genitalia (XLAG) and developmental epileptic 
      encephalopathy-1 (DEE1) are caused by mutations in the Aristaless-related 
      homeobox (ARX) gene, which encodes a transcription factor responsible for brain 
      development. It has been unknown whether the phenotypically diverse XLAG and DEE1 
      phenotypes may converge on shared pathways. To address this question, a 
      label-free quantitative proteomic approach was applied to the neonatal brain of 
      Arx knockout (ArxKO/Y) and knock-in polyalanine (Arx(GCG)7/Y) mice that are 
      respectively models for XLAG and DEE1. Gene ontology and protein-protein 
      interaction analysis revealed that cytoskeleton, protein synthesis and splicing 
      control are deregulated in an allelic-dependent manner. Decreased alpha-tubulin 
      content was observed both in Arx mice and Arx/alr-1(KO) Caenorhabditis elegans 
      ,and a disorganized neurite network in murine primary neurons was consistent with 
      an allelic-dependent secondary tubulinopathy. As distinct features of Arx(GCG)7/Y 
      mice, we detected eIF4A2 overexpression and translational suppression in cortex 
      and primary neurons. Allelic-dependent differences were also established in 
      alternative splicing (AS) regulated by PUF60 and SAM68. Abnormal AS repertoires 
      in Neurexin-1, a gene encoding multiple pre-synaptic organizers implicated in 
      synaptic remodelling, were detected in Arx/alr-1(KO) animals and in Arx(GCG)7/Y 
      epileptogenic brain areas and depolarized cortical neurons. Consistent with a 
      conserved role of ARX in modulating AS, we propose that the allelic-dependent 
      secondary synaptopathy results from an aberrant Neurexin-1 repertoire. Overall, 
      our data reveal alterations mirroring the overlapping and variant effects caused 
      by null and polyalanine expanded mutations in ARX. The identification of these 
      effects can aid in the design of pathway-guided therapy for ARX endophenotypes 
      and NDDs with overlapping comorbidities.
CI  - (c) The Author(s) 2022. Published by Oxford University Press. All rights reserved. 
      For Permissions, please email: journals.permissions@oup.com.
FAU - Drongitis, Denise
AU  - Drongitis D
AD  - Institute of Genetics and Biophysics ;;Adriano Buzzati-Traverso'', National 
      Research Council of Italy, 80131, Naples, Italy.
FAU - Caterino, Marianna
AU  - Caterino M
AD  - Department of Molecular Medicine and Medical Biotechnology, University of Naples 
      "Federico II", 80131 Naples, Italy.
AD  - CEINGE - Biotecnologie Avanzate s.c.a.r.l., 80145 Naples, Italy.
FAU - Verrillo, Lucia
AU  - Verrillo L
AD  - Institute of Genetics and Biophysics ;;Adriano Buzzati-Traverso'', National 
      Research Council of Italy, 80131, Naples, Italy.
FAU - Santonicola, Pamela
AU  - Santonicola P
AD  - Institute of Biosciences and BioResources, National Research Council of Italy, 
      80131, Naples, Italy.
FAU - Costanzo, Michele
AU  - Costanzo M
AD  - Department of Molecular Medicine and Medical Biotechnology, University of Naples 
      "Federico II", 80131 Naples, Italy.
AD  - CEINGE - Biotecnologie Avanzate s.c.a.r.l., 80145 Naples, Italy.
FAU - Poeta, Loredana
AU  - Poeta L
AD  - Institute of Genetics and Biophysics ;;Adriano Buzzati-Traverso'', National 
      Research Council of Italy, 80131, Naples, Italy.
AD  - Department of Science, University of Basilicata, 85100 Potenza, Italy.
FAU - Attianese, Benedetta
AU  - Attianese B
AD  - Institute of Genetics and Biophysics ;;Adriano Buzzati-Traverso'', National 
      Research Council of Italy, 80131, Naples, Italy.
FAU - Barra, Adriano
AU  - Barra A
AD  - Institute of Genetics and Biophysics ;;Adriano Buzzati-Traverso'', National 
      Research Council of Italy, 80131, Naples, Italy.
FAU - Terrone, Gaetano
AU  - Terrone G
AD  - Department of Translational Medicine, Child Neurology Unit, University of Naples 
      "Federico II", 80131 Naples, Italy.
FAU - Lioi, Maria Brigida
AU  - Lioi MB
AD  - Department of Science, University of Basilicata, 85100 Potenza, Italy.
FAU - Paladino, Simona
AU  - Paladino S
AD  - Department of Molecular Medicine and Medical Biotechnology, University of Naples 
      "Federico II", 80131 Naples, Italy.
FAU - Di Schiavi, Elia
AU  - Di Schiavi E
AD  - Institute of Biosciences and BioResources, National Research Council of Italy, 
      80131, Naples, Italy.
FAU - Costa, Valerio
AU  - Costa V
AD  - Institute of Genetics and Biophysics ;;Adriano Buzzati-Traverso'', National 
      Research Council of Italy, 80131, Naples, Italy.
FAU - Ruoppolo, Margherita
AU  - Ruoppolo M
AD  - Department of Molecular Medicine and Medical Biotechnology, University of Naples 
      "Federico II", 80131 Naples, Italy.
AD  - CEINGE - Biotecnologie Avanzate s.c.a.r.l., 80145 Naples, Italy.
FAU - Miano, Maria Giuseppina
AU  - Miano MG
AUID- ORCID: 0000-0003-1396-9673
AD  - Institute of Genetics and Biophysics ;;Adriano Buzzati-Traverso'', National 
      Research Council of Italy, 80131, Naples, Italy.
LA  - eng
GR  - P40 OD010440/OD/NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (ARX protein, mouse)
RN  - 0 (Homeodomain Proteins)
RN  - 0 (Transcription Factors)
RN  - 63231-63-0 (RNA)
SB  - IM
MH  - Animals
MH  - *Brain Diseases/genetics
MH  - Genes, Homeobox
MH  - Homeodomain Proteins/genetics/metabolism
MH  - *Lissencephaly/genetics
MH  - Mice
MH  - Microtubules/metabolism
MH  - Mutation
MH  - Proteomics
MH  - RNA
MH  - Transcription Factors/genetics
PMC - PMC9169459
EDAT- 2022/01/31 06:00
MHDA- 2022/06/09 06:00
PMCR- 2022/01/31
CRDT- 2022/01/30 20:37
PHST- 2021/10/30 00:00 [received]
PHST- 2022/01/10 00:00 [revised]
PHST- 2022/01/26 00:00 [accepted]
PHST- 2022/01/31 06:00 [pubmed]
PHST- 2022/06/09 06:00 [medline]
PHST- 2022/01/30 20:37 [entrez]
PHST- 2022/01/31 00:00 [pmc-release]
AID - 6517527 [pii]
AID - ddac028 [pii]
AID - 10.1093/hmg/ddac028 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2022 Jun 4;31(11):1884-1908. doi: 10.1093/hmg/ddac028.