Disease-related pathways in NDD disorders

A disproportional large number of neurodevelopmental disorders (NDDs) including malformations of cortical development (MCD), developmental epileptic encephalopathies (DEE), intellectual disability (ID) and autism spectrum disorders (ASD) is caused by mutations in genes encoding transcription factors and chromatin modifiers. Our laboratory focuses on the genetic and molecular aspects of a group of X-chromosome genes proved that they belong to an interconnected transcriptional axes underpinning multiple NDDs with clinical overlap.

On the basis of our previous work on rare X-linked NDDs, we apply in vivo and in vitro approaches and omics technologies to address the following questions:

• why different mutations in ARX and KDM5C cause diverse neuronal phenotypes with shared phenotypic spectra;
• which is the pathological role of gene targets of ARX and KDM5C involved in other NDDs.

New therapies for ARX-related epilepsy

Developmental epileptic encephalopathy type 1 (DDE1) associated with ARX polyalanine expansions is largely pharmaco-resistant. We are currently investigating the impact of ARX polyalanine expansions in the epileptogenesis and how this knowledge could help the discovery of molecular-targeted therapies. We are evaluating a number of small molecules including epi-drugs and biomolecules that allow simultaneous to counteract defects in ARX-dependent paths and stop and/or ameliorate behavioral epileptic phenotype in Arx-polyalanine mice.

Scientific committee:

• http://www.igb.cnr.it/19thxlid/
• http://www.neapolitanbraingroup.it/
• https://scn2a-italia.it/

Guest editor:

Poeta L, Malacarne M, Padula A, Drongitis D, Verrillo L, Chiariello AM, Nicodemi M, Lioi MB, Piccione M, Coviello D, Miano MG. Further Delineation of Duplications of ARX Locus Detected in Male Patients with Varying Degrees of Intellectual Disability. Int J Mol Sci. 2022 Mar 13;23(6):3084

Drongitis D, Caterino M, Verrillo L, Santonicola P, Costanzo M, Poeta L, Attianese B, Barra A, Terrone G, Lioi MB, Paladino S, Di Schiavi E, Costa V, Ruoppolo M, Miano M. G. Deregulation of microtubule organization and RNA metabolism in Arx models for Lissencephaly and Developmental epileptic encephalopathy. Hum Mol Genet. 2022 Jan 31:ddac028. doi: 10.1093/hmg/ddac028.

Poeta L, Padula A, Lioi MB, van Bokhoven H, Miano MG. Analysis of a Set of KDM5C Regulatory Genes Mutated in Neurodevelopmental Disorders Identifies Temporal Coexpression Brain Signatures. Genes. 2021 Jul 18;12(7):1088. doi: 10.3390/genes12071088.

Verrillo L, Mangano E, Drongitis D, Merelli I, Pischedda F, Piccoli G, Consolandi C, Bordoni R, Miano MG. A reliable strategy for single-cell RNA sequencing analysis using cryoconserved primary cortical cells. J Neurosci Methods. 2021 Jan 1;347:108960. doi: 10.1016/j.jneumeth.2020.108960.

Petrone P, Giordano G, Vezzoli E, Pensa A, Castaldo G, Graziano V, Sirano F, Capasso E, Quaremba G, Vona A, Miano MG, Savino S, Niola M. Preservation of neurons in an AD 79 vitrified human brain. PLoS One. 2020 Oct 6;15(10):e0240017. doi: 10.1371/journal.pone.0240017.

Poeta L, Padula A, Attianese B, Valentino M, Verrillo L, Filosa S, Shoubridge C, Barra A, Schwartz CE, Christensen J, van Bokhoven H, Helin K, Lioi MB, Collombat P, Gecz J, Altucci L, Di Schiavi E, Miano MG. Histone demethylase KDM5C is a SAHA-sensitive central hub at the crossroads of transcriptional axes involved in multiple neurodevelopmental disorders. Hum Mol Genet. 2019 Dec 15;28(24):4089-4102. doi: 10.1093/hmg/ddz254.

Poeta L, Fusco F, Drongitis D, Shoubridge C, Manganelli G, Filosa S, Paciolla M, Courtney M, Collombat P, Lioi MB, Gecz J, Ursini MV, Miano MG. A regulatory path associated with X-linked intellectual disability and epilepsy links KDM5C to the polyalanine expansions in ARX. Am J Hum Genet. 2013 Jan 10;92(1):114-25. doi: 10.1016/j.ajhg.2012.11.008.

Paciolla M, Boni R, Fusco F, Pescatore A, Poeta L, Ursini MV, Lioi MB, Miano MG. Nuclear factor-kappa-B-inhibitor alpha (NFKBIA) is a developmental marker of NF-κB/p65 activation during in vitro oocyte maturation and early embryogenesis. Hum Reprod. 2011 May;26(5):1191-201. doi: 10.1093/humrep/der040.

Laperuta C, Spizzichino L, D'Adamo P, Monfregola J, Maiorino A, D'Eustacchio A, Ventruto V, Neri G, D'Urso M, Chiurazzi P, Ursini MV, Miano MG. MRX87 family with Aristaless X dup24bp mutation and implication for polyAlanine expansions. BMC Med Genet. 2007 May 4;8:25. doi: 10.1186/1471-2350-8-25.

Annunziata I, Lanzara C, Conte I, Zullo A, Ventruto V, Rinaldi MM, D'Urso M, Casari G, Ciccodicola A, Miano MG. Mapping of MRX81 in Xp11.2-Xq12 suggests the presence of a new gene involved in nonspecific X-linked mental retardation. Am J Med Genet A. 2003 Apr 30;118A(3):217-22. doi: 10.1002/ajmg.a.10144.

Ciccodicola A, D'Esposito M, Esposito T, Gianfrancesco F, Migliaccio C, Miano MG, Matarazzo MR, Vacca M, Franzè A, Cuccurese M, Cocchia M, Curci A, Terracciano A, Torino A, Cocchia S, Mercadante G, Pannone E, Archidiacono N, Rocchi M, Schlessinger D, D'Urso M. Differentially regulated and evolved genes in the fully sequenced Xq/Yq pseudoautosomal region. Hum Mol Genet. 2000 Feb 12;9(3):395-401. doi: 10.1093/hmg/9.3.395.

Vervoort R, Lennon A, Bird AC, Tulloch B, Axton R, Miano MG, Meindl A, Meitinger T, Ciccodicola A, Wright AF. Mutational hot spot within a new RPGR exon in X-linked retinitis pigmentosa. Nat Genet. 2000 Aug;25(4):462-6. doi: 10.1038/78182. PMID: 10932196

Education

PhD in Systematic Biology, Faculty of Biological Sciences, University of Naples Federico II, Naples, 2003.

Master of Science in Statistical Genetics, Faculty of Medicine, University of Pavia, European Schools for Advanced Studies in Molecular Medicine and Genetic Epidemiology, Pavia, 2000.

Specialist Degree summa cum laude in Medical Genetics, Faculty of Medicine at the University of Rome La Sapienza, Rome, 1997.

Degree summa cum laude in Biology, Faculty of Biological Sciences at the University of Naples Federico II, Naples, 1990.

Research Experience

CNR Senior Researcher at Institute of Genetics and Biophysics “Adriano Buzzati Traverso”, Naples, 2021 - Present.

CNR-Short Term Fellow visiting the University of Adelaide. Australia. 2013.

Group Leader in Human Molecular Neurogenetics, 2006 - Present.

CNR Researcher at Institute of Genetics and Biophysics “Adriano Buzzati Traverso”, Naples, 2001

International Institute of Genetics and Biophysics, Naples, Telethon and MIUR Fellowship, 1998 - 2000.

Medical Research Council Fellow visiting the Human Genetic Unit−MRC, Edinburgh, UK.1999.

EMBO short-term Fellow visiting the Human Genetic Unit at Medical Research Council (MRC), Edinburgh, UK,1998.

International Institute of Genetics and Biophysics, Naples, CNR Fellowship, 1996.

National Cancer Institute, Naples, 1995. Fellowship.

University of Naples “Federico II”, Faculty of Medicine, Cytogenetic and Prenatal Diagnosis. Naples, 1992 -1994.

International Institute of Genetics and Biophysics-CNR, Naples, Post−degree Training, 1991-1992.