This thesis studied the genetic causes and molecular mechanisms leading to malformations of cortical development (MCD), to enable a new gene-based MCD classification method, and to improve counselling and the diagnostic yield in clinic. First, mutations in genes (COL3A1 and ZIC1) earlier described in other diseases were linked to cortical development. We identified bi-allelic COL3A1 variants as novel genetic cause for cobblestone malformation and detected a novel dominant ZIC1 variant leading to microcephaly and cerebellar malformations, hereby expanding the clinical phenotype previously associated with this gene (craniosynostosis).
Besides expansion of clinical phenotypes we studied the function(s) of Rotatin (RTTN) in cortical development in detail and made a revision of all clinical phenotypes in reported and novel cases (n=28). We found that RTTN mutants lack expression of Rotatin at the centrosome. This resulted in mitotic failure with centrosome amplification, multipolar cell division, aneuploidy and apoptosis in affected individuals, underlying the observed proliferation/apoptosis disorders (microcephaly and short stature). RTTN mutants also displayed structural or functional anomalies of ciliogenesis. Lastly, we show that RTTN localized at the centrosome in the leading edge of migrating iPSC derived neurons and colocalized with MYH10. This thesis also described a completely new gene TMX2, elucidated its function and showed the involvement of a novel protein family (PDIs) in MCDs. Bi-allelic TMX2 variants led to microcephaly, polymicrogyria and drug-resistant epilepsy. TMX2 mutants impaired protein folding, resulting in mitochondrial failure with decreased reserve capacity to account for oxidative stress. TMX2 mutants dimerized, instead of staying in the monomeric form, mimicking the proteins’ physiological response to oxidative stimuli.
Datum Prijs12 sep 2019
Toekennende instantie
  • Vrije Universiteit Brussel
BegeleiderAnna Jansen (Promotor), Katrien Stouffs (Promotor), Grazia Mancini (Co-promotor), Alexander Gheldof (Co-promotor), Robert Hofstra (Jury), Laurent Nguyen (Jury), Hilde Van Esch (Jury), Claudia Spits (Jury), Ilse Smolders (Jury) & Leo van Grunsven (Jury)

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