Neurodevelopmental centrosomopathies and golgipathies

The centrosome and the Golgi apparatus are dynamic organelles critical for the maintenance of cellular homeostasis and the regulation of the cell cycle. Despite their ubiquitous nature, the disturbance of their structure and/or their functions called centrosomopathies or Golgipathies, is frequently associated with defects in cerebral growth and maturation (El Ghouzzi, Nat Commun 2022), in particular with microcephaly, one of the most common neurological sign among neurodevelopmental disorders.

Our group has largely contributed to the identification of several microcephaly genes associated with centrosomopathies (Passemard, Neurology 2009; Nicholas, Nat Genet 2010; Harding, Am J Hum Genet 2016; Létard, Hum Mutat 2018) or Golgipathies (Dimitrov , Hum Mol Genet 2009; Dupuis, Hum Mutat 2013; Izumi, Am J Hum Genet 2016; Uwineza, Eur J Med Genet 2019). The products of genes implicated in centrosomopathies clearly have a role in cell cycle regulation and in the dynamics of the mitotic spindle during the division of neural progenitors, while those of Golgipathies genes appear to be important for the trafficking of pre or post-Golgi vesicles. This suggests that very different patho-mechanisms can lead to microcephaly.

Our group is interested in

i. the phenotypic and molecular characterization of new centrosomopathies and Golgipathies
ii. understanding the pathophysiological roles of the centrosome and the Golgi apparatus in the development of microcephaly

Our experimental approaches include brain imaging, modeling of brain development using organoids derived from human induced pluripotent cells (hiPSCs) from patients and mouse models knocked out for genes of interest.

 

Members

Albert Alexandra, Inserm Assistant Engineer

Drunat Séverine, Geneticist

El Ghouzzi Vincent, CNRS Researcher

Jacquier Sandrine, Inserm Assistant Engineer

Lebon Sophie, Inserm Research Engineer

Le Guilloux Gwendoline, Inserm Assistant Engineer

Levy Jonathan, PH APHP

Masson Justine, CNRS Researcher

Passemard Sandrine, Professor & Child Neurologist

Rak Malgorzata, CNRS Researcher

Verloes Alain, Professor & Geneticist

Vial Yoann, University Hospital Doctor

 

 

Main Publications

  1. Lebon S., Bruneel A., Drunat S., Albert A., Csaba Z., Elmaleh M., Ntorkou A., Ténier Y., Fenaille F., Gressens P., Passemard S., Boespflug-Tanguy O., Dorboz I., El Ghouzzi V. A biallelic variant in GORASP1 causes a novel Golgipathy with glycosylation and mitotic defects. Life Sci. Alliance, 2025 Feb 11;8(4)
  2. Gins C., Guimiot F., Drunat S., Prévost C., Rosenblatt J., Capri Y., Letard P., Khung-Savatovsky S., Mahi Henni M.A., Chafai Elalaoui S., Alison M., Guilmin Crepon S., Gressens P., Verloes A., Basto R., El Ghouzzi V.,Passemard S. Radial microbrain (micrencephaly) is caused by a recurrent variant in the RTTN gene. Neurol Genet., 2025, in press
  3. Pedraza M., Grampa V., Scotto-Lomassese S., Puech J., Muzerelle A., Mohammad A., Renier N., Métin C., Masson J. The ciliary kinesin KIF7 controls the development of the cerebral cortex by acting differentially on SHH-signaling in dorsal and ventral forebrain. eLife, 2025, in press
  4. El Ghouzzi V., Boncompain G. Golgipathies reveal the critical role of the sorting machinery in brain and skeletal development Nat. Commun., 2022, 13, 7397.
  5. Farcy S., Albert A., Gressens P., Baffet A.*, El Ghouzzi V*. Cortical Organoids to Model Microcephaly. Cells,  2022 , 11, 2135. * co-Last
  6. Ruaud L., Drunat S., Elmaleh-Berges M., Ernault A., Crepon SG., El Ghouzzi V., Auvin S., Verloes A., Passemard S. Neurological outcome in WDR62 primary microcephaly. Dev. Med Child Neurol., 2022, 64, 509-517.
  7. Masson J., El Ghouzzi V. Golgi dysfunctions in ciliopathies Cells, 2022, 11, 2773.
  8. Nasser H., Vera L., Elmaleh-Bergès M., Steindl K., Létard P., Teissier N., Ernault A., Guimiot F., Afenjar A., Moutard M.L., Héron D., Alembik Y., Montchilova M., Milani P., Rigaudière F., Kubis N., Pouvreau N., Gressens P., Verloes A., Rauch A., El Ghouzzi V., Drunat S., Passemard S. CDK5RAP2 primary microcephaly is associated with hypothalamic, retinal and cochlear developmental defects. J. Med. Genet. 2020, 57, 389-399
  9. Passemard S., Perez F., Gressens P., El Ghouzzi V. Endoplasmic reticulum and Golgi stress in microcephaly. Cell Stress, 2019, 3, 369-384.
  10. Uwineza A., Caberg J.H., Hitayezu J., Wenric S., Mutesa L., Vial Y., Drunat S., Passemard S., Verloes A., El Ghouzzi V., Bours V. VPS51 biallelic variants cause microcephaly with brain malformations. Eur. J. Med. Genet., 2019, 62, 103704-708.
  11. Rasika S., Passemard S., Verloes A., Gressens P., El Ghouzzi V. Golgipathies in neurodevelopment : A new view of old defects. Dev. Neurosci., 2018, 40, 396-416.
  12. Létard P., Drunat S., Vial Y., Duerinckx S., Ernault A., Amram D., Arpin S., Bertoli M., Busa T., Ceulemans B., Desir J., Doco-Fenzy M., Chafai Elalaoui S., Devriendt K., Faivre L., Francannet C., Geneviève D., Gérard M., Gitiaux C., Julia S., Lebon S., Lubala T., Mathieu-Dramard M., Maurey H., Metreau J., Nasserereddine S., Nizon M., Pierquin G., Pouvreau N., Rivier-Ringenbach C., Rossi M., Schaefer E., Sefiani A., Sigaudy S., Sznajer Y., Tunca Y., Guilmin Crepon S., Alberti C., Elmaleh-Bergès M., Benzacken B., Wollnick B., Woods G, Rauch A., Abramowicz A., El Ghouzzi V., Gressens P., Verloes A., Passemard S. Autosomal recessive primary microcephaly due to ASPM mutations: an update. Hum. Mutat., 2018, 39, 319-332.
  13. Patwardhan D., Mani S., Passemard S., Gressens P., El Ghouzzi V. STIL balancing microcephaly and cancer. Cell Death Dis., 2018, 9, 65-76.
  14. Passemard S., Perez F., Colin-Lemesre E., Rasika S., Gressens P., El Ghouzzi V. Golgi trafficking defects in postnatal microcephaly: The evidence for “Golgipathies”. Prog. Neurobiol., 2017, 153, 46-63.
  15. Cavallin M., Rujano M.A., Bednarek N., Medina-Cano D., Bernabe Gelot A., Drunat S., Maillard C., Garfa-Traore M., Bole C., Nitschké P., Beneteau C., Besnard T., Cogné B., Eveillard M., Kuster A., Poirier K., Verloes A., Martinovic J., Bidat L., Rio M., Lyonnet S., Reilly M.L., Boddaert N., Jenneson-Liver M., Motte J., Doco-Fenzy M., Chelly J., Attie-Bitach T., Simons M., Cantagrel V., Passemard S., Baffet A., Thomas S., Bahi-Buisson N. WDR81 mutations cause extreme microcephaly and impair mitotic progression in human fibroblasts and Drosophila neural stem cells. Brain, 2017, 140, 2597-2609.
  16. Passemard S., Verloes A., Billette de Villemeur T., Boespflug O., Hernandez K., Laurent M., Isidor B., Alberti C., Pouvreau N., Drunat S., Gérard B., El Ghouzzi V., Gallego J., Elmaleh-Bergès M., Huttner W.B., Eliez S., Gressens P., Schaer M. Abnormal spindle-like microcephaly (ASPM) mutations strongly disrupt neocortex but spare hippocampus and long-term memory. Cortex, 2016, 74, 158-176.
  17. Izumi K., Brett M., Nishi E., Drunat S., Tan E., Fujiki K., Lebon S., Cham B., Masuda K., Arakawa M., Jacquinet A., Yamazumi Y., Chen S., Verloes A., Okada Y., Nakamura T., Akiyama T., Gressens P., Foo R., Passemard S., Tan E., El Ghouzzi V.*, Shirahige K*. ARCN1 mutations cause a recognizable craniofacial syndrome due to COPI-mediated transport defects. Am. J. Hum. Genet., 2016, 99, 451-459. * co-Last.
  18. Harding B.N., Moccia A., Soukarieh O., Tubeuf H., Drunat S., Chitty L.S., Verloes A., Gressens P., El Ghouzzi V., Joriot S., Passemard S., Di Cunto F., Martins A., Bielas S.L. Mutations in Citron Kinase cause recessive microlissencephaly with multinucleated neurons.  Am. J. Hum. Genet., 2016, 99, 511-520.
  19. El Ghouzzi V., Bianchi F.T., Molineris I., Mounce B.C., Berto G.E., Rak M., Lebon S., Aubry L., Tocco C., Gai M., Chiotto A.M.A., Sgrò, Pallavicini G., Simon-Loriere E., Passemard S., Vignuzzi M., Gressens P., Di Cunto F. ZIKA Virus elicits P53 activation and genotoxic stress in human neural progenitors similar to mutations involved in severe forms of genetic microcephaly. Cell Death Dis., 2016, 7, e2440.
  20. Dupuis N., Fafouri A., Bayot A., Kumar K., Lecharpentier T., Ball G., Edwards A.D., Bernard V., Dournaud P., Drunat S., Vermelle-Andrzejewski M., Vilain C., Abramowicz M., Désir J., Bonaventure J., Gareil N., Boncompain G., Csaba Z., Perez F., Passemard S., Gressens P., El Ghouzzi V. Dymeclin deficiency causes postnatal microcephaly, hypomyelination and reticulum-to-Golgi trafficking defects in mice and humans. Hum. Mol. Genet., 2015, 24, 2771-2783.
  21. Srivastava R., Kumar M., Peineau S., Csaba Z., Mani S., Gressens P., El Ghouzzi V. Conditional induction of Math1 specifies embryonic stem cells to cerebellar granule neuron lineage and promotes differentiation into mature granule neurons. Stem Cells, 2013, 31, 652-665.

Contacts

Vincent El Ghouzzi, PhD, CRHC CNRS
UMR Inserm 1141 – NeuroDiderot
Hôpital Robert Debré
48 boulevard Sérurier
75019 Paris
vincent.elghouzzi@inserm.fr
Sandrine Passemard, MD PhD, PR Paris 7
Service de Génétique and UMR Inserm 1141 – NeuroDiderot
Hôpital Robert Debré
48 boulevard Sérurier
75019 Paris
sandrine.passsemard@inserm.fr

Read more