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Research group/lab  |  P.I. Grazia M.S. Mancini

Genetics of brain malformations

We focus on the genetic mutations involved in brain malformation and on the characterization of the disease mechanism, with the goal to improve diagnosis and medical care.

About our research group/lab

Our research

Brain development disorders

The development of the brain cortex is a complex process, which is strictly regulated in time and space. Rare genetic mutations can have consequences for the intellectual development, motor skills such as speech and walking, and behaviour, leading to a broad range of intellectual disability, autism, cerebral palsy and seizures. We focus on malformations of the cerebral cortex, classified on radiological (MRI) pattern, such as lissencephaly, nodular heterotopia, polymicrogyria, microcephaly, megalencephaly, schizencephaly and porencephaly. All of these are rare, and very little is known about the cause and disease mechanisms. We aim at discovering new genes and disease mechanisms.

The research 

Stored material of undiagnosed patients is used to test novel candidate genes with WES/WGS, RNAseq, and functional biochemical tests at cell and stem cell biological level. The focus lies on specific mechanisms involved in brain development, such as regulation of cell-cell interaction (e.g. formation and function of primary cilia and cell migration), cell proliferation (regulation of mitosis) and regulation of cell death (apoptosis). Broad national and international collaborations allow confirmation and validation in additional individuals.

First picture Genetics of brain malformations


Second picture Genetics of brain malformations

Main achievements

In this project, we have already discovered brain malformations caused by mutations in the following genes:

  • AP4M1
  • IER3IP1
  • RTTN
  • COL4A2
  • USP18
  • MOCS3
  • INTS1
  • INTS8
  • MACF1
  • CARS
  • SMPD4
  • TMX2

Our group has also collaborated to the characterization of brain malformations and of human mutations in the following genes:

  • ACTB
  • PIK3CA
  • AKT3
  • CCND2
  • SCN3A
  • APC2
  • EML1
  • ISPD
  • CSTB
  • PNKP
  • ZIC1

Our projects

Ongoing projects:

  • Microtubule-lipid crosstalk during neuronal cytokinesis
    (ZonMW TOP # 91217045, co-PI)
  • Zebrafish modeling and transcriptome analysis of patient cells for new pathogenic mechanisms of primary microcephaly (Erasmus MC, Clinical Genetics).

Key Publications

TMX2 is a crucial regulator of cellular redox state and its dysfunction causes severe brain developmental abnormalities.Laura Virginia Vandervore, Rachel Schot, Chiara Milanese, Daphne J Smits, Esmee Kasteleijn, Andrew E Fry, Daniela T Pilz, Stefanie Brock, Esra Börklü-Yücel, Marco Post, Nadia Bahi-Buisson, Maria José Sánchez-Soler, Marjon van Slegtenhorst, Boris Keren, Alexandra Afenjar, Stephanie Coury, Wen-Hann Tan, Renske Oegema, Linda S. De Vries, Katherine A. Fawcett, Peter G.J. Nikkels, Aida Bertoli-Avella, Amal Al Hashem, Abdulmalik A. Alwabel, Kalthoum Tlili-Graiess, Stephanie Efthymiou, Faisal Zafar, Nuzhat Rana, Farah Bibi, Henry Houlden, Reza Maroofian, Richard E. Person, Amy Crunk, Juliann M. Savatt, Lisbeth Turner, Mohammad Doosti, Ehsan Ghayoor Karimiani, Nebal Waill Saadi, Javad Akhondian, Maarten H. Lequin, Hülya Kayserili, Peter J. van der Spek, Anna C. Jansen, Johan M. Kros, Robert M. Verdijk, Nataša Jovanov Milošević, Maarten Fornerod, Pier Giorgio Mastroberardino, Grazia Maria Simonetta Mancini. (2019). Am J Hum Genet 2019, November 14th online.

Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis.Magini P, Smits DJ, Vandervore L, Schot R, Columbaro M, Kasteleijn E, van der Ent M, Palombo F, Lequin MH, Dremmen M, de Wit MCY, Severino M, Divizia MT, Striano P, Ordonez-Herrera N, Alhashem A, Al Fares A, Al Ghamdi M, Rolfs A, Bauer P, Demmers J, Verheijen FW, Wilke M, van Slegtenhorst M, van der Spek PJ, Seri M, Jansen AC, Stottmann RW, Hufnagel RB, Hopkin RJ, Aljeaid D, Wiszniewski W, Gawlinski P, Laure-Kamionowska M, Alkuraya FS, Akleh H, Stanley V, Musaev D, Gleeson JG, Zaki MS, Brunetti-Pierri N, Cappuccio G, Davidov B, Basel-Salmon L, Bazak L, Shahar NR, Bertoli-Avella A, Mirzaa GM, Dobyns WB, Pippucci T, Fornerod M, Mancini GMS. Am J Hum Genet. (2019). Am J Hum Genet. 2019 Oct 3;105(4):689-705.

Heterogeneous clinical phenotypes and cerebral malformations reflected by rotatin cellular dynamics.Vandervore LV, Schot R, Kasteleijn E, Oegema R, Stouffs K, Gheldof A, Grochowska MM, van der Sterre MLT, van Unen LMA, Wilke M, Elfferich P, van der Spek PJ, Heijsman D, Grandone A, Demmers JAA, Dekkers DHW, Slotman JA, Kremers GJ, Schaaf GJ, Masius RG, van Essen AJ, Rump P, van Haeringen A, Peeters E, Altunoglu U, Kalayci T, Poot RA, Dobyns WB, Bahi-Buisson N, Verheijen FW, Jansen AC, Mancini GMS. (2019). Brain. 2019 Apr 1;142(4):867-884.

Cysteinyl-tRNA Synthetase Mutations Cause a Multi-System, Recessive Disease That Includes Microcephaly, Developmental Delay, and Brittle Hair and Nails.Kuo ME, Theil AF, Kievit A, Malicdan MC, Introne WJ, Christian T, Verheijen FW, Smith DEC, Mendes MI, Hussaarts-Odijk L, van der Meijden E, van Slegtenhorst M, Wilke M, Vermeulen W, Raams A, Groden C, Shimada S, Meyer-Schuman R, Hou YM, Gahl WA, Antonellis A, Salomons GS, Mancini GMS. (2019). Am J Hum Genet. 2019 Mar 7;104(3):520-529.

MACF1 Mutations Encoding Highly Conserved Zinc-Binding Residues of the GAR Domain Cause Defects in Neuronal Migration and Axon Guidance.Dobyns WB, Aldinger KA, Ishak GE, Mirzaa GM, Timms AE, Grout ME, Dremmen MHG, Schot R, Vandervore L, van Slegtenhorst MA, Wilke M, Kasteleijn E, Lee AS, Barry BJ, Chao KR, Szczałuba K, Kobori J, Hanson-Kahn A, Bernstein JA, Carr L, D'Arco F, Miyana K, Okazaki T, Saito Y, Sasaki M, Das S, Wheeler MM, Bamshad MJ, Nickerson DA; University of Washington Center for Mendelian Genomics; Center for Mendelian Genomics at the Broad Institute of MIT and Harvard, Engle EC, Verheijen FW, Doherty D, Mancini GMS. (2018). Am J Hum Genet. 2018 Dec 6;103(6):1009-1021.


Collaboration within Erasmus MC

  • Department of Cell Biology
  • Department of Child Neurology
  • Department of Radiology
  • Department of Bioinformatics
  • ENCORE expertise centrum

Collaboration outside of Erasmus MC

Within the European Network on Brain Malformations (neuro-MIG), academic and patient organizations and private companies from 31 European and intercontinental countries are affiliated, including about 130 member researchers. Grazia Mancini has been the main proposer of the COST Action (CA16118, running from 2017 to 2021) supporting this Network and is the chair of the management committee.

Funding & Grants

Our team

  • Grazia M.S. Mancini, MD PhD, PI
  • Rachel Schot, BSc, technical biochemistry and molecular biology
  • Daphne Smits, MD, PhD student
  • Jordy Dekker, MD, shared PhD student
  • Frans Verheijen, PhD, clinical molecular biochemist

Research team of Genetics of brain malformations

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