Affordable Access

Publisher Website

Deregulation of microtubule organization and RNA metabolism in Arx models for lissencephaly and developmental epileptic encephalopathy.

  • Drongitis, Denise1
  • Caterino, Marianna2, 3
  • Verrillo, Lucia1
  • Santonicola, Pamela4
  • Costanzo, Michele2, 3
  • Poeta, Loredana1, 5
  • Attianese, Benedetta1
  • Barra, Adriano1
  • Terrone, Gaetano6
  • Lioi, Maria Brigida5
  • Paladino, Simona2
  • Di Schiavi, Elia4
  • Costa, Valerio1
  • Ruoppolo, Margherita2, 3
  • Miano, Maria Giuseppina1
  • 1 Institute of Genetics and Biophysics ``Adriano Buzzati-Traverso'', National Research Council of Italy, 80131, Naples, Italy. , (Italy)
  • 2 Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", 80131 Naples, Italy. , (Italy)
  • 3 CEINGE - Biotecnologie Avanzate s.c.a.r.l., 80145 Naples, Italy. , (Italy)
  • 4 Institute of Biosciences and BioResources, National Research Council of Italy, 80131, Naples, Italy. , (Italy)
  • 5 Department of Science, University of Basilicata, 85100 Potenza, Italy. , (Italy)
  • 6 Department of Translational Medicine, Child Neurology Unit, University of Naples "Federico II", 80131 Naples, Italy. , (Italy)
Published Article
Human Molecular Genetics
Oxford University Press
Publication Date
Jun 04, 2022
DOI: 10.1093/hmg/ddac028
PMID: 35094084


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 α-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. © The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]

Report this publication


Seen <100 times