@phdthesis{12364,
  abstract     = {Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders characterized by behavioral symptoms such as problems in social communication and interaction, as
well as repetitive, restricted behaviors and interests. These disorders show a high degree
of heritability and hundreds of risk genes have been identifed using high throughput
sequencing technologies. This genetic heterogeneity has hampered eforts in understanding
the pathogenesis of ASD but at the same time given rise to the concept of convergent
mechanisms. Previous studies have identifed that risk genes for ASD broadly converge
onto specifc functional categories with transcriptional regulation being one of the biggest
groups. In this thesis, I focus on this subgroup of genes and investigate the gene regulatory
consequences of some of them in the context of neurodevelopment.
First, we showed that mutations in the ASD and intellectual disability risk gene Setd5 lead
to perturbations of gene regulatory programs in early cell fate specifcation. In addition,
adult animals display abnormal learning behavior which is mirrored at the transcriptional
level by altered activity dependent regulation of postsynaptic gene expression. Lastly,
we link the regulatory function of Setd5 to its interaction with the Paf1 and the NCoR
complex.
Second, by modeling the heterozygous loss of the top ASD gene CHD8 in human cerebral
organoids we demonstrate profound changes in the developmental trajectories of both
inhibitory and excitatory neurons using single cell RNA-sequencing. While the former
were generated earlier in CHD8+/- organoids, the generation of the latter was shifted to
later times in favor of a prolonged progenitor expansion phase and ultimately increased
organoid size.
Finally, by modeling heterozygous mutations for four ASD associated chromatin modifers,
ASH1L, KDM6B, KMT5B, and SETD5 in human cortical spheroids we show evidence of
regulatory convergence across three of those genes. We observe a shift from dorsal cortical
excitatory neuron fates towards partially ventralized cell types resembling cells from the
lateral ganglionic eminence. As this project is still ongoing at the time of writing, future
experiments will aim at elucidating the regulatory mechanisms underlying this shift with
the aim of linking these three ASD risk genes through biological convergence.},
  author       = {Dotter, Christoph},
  issn         = {2663-337X},
  pages        = {152},
  publisher    = {Institute of Science and Technology Austria},
  title        = {{Transcriptional consequences of mutations in genes associated with Autism Spectrum Disorder}},
  doi          = {10.15479/at:ista:12094},
  year         = {2022},
}

@article{691,
  abstract     = {Background: Transport protein particle (TRAPP) is a multisubunit complex that regulates membrane trafficking through the Golgi apparatus. The clinical phenotype associated with mutations in various TRAPP subunits has allowed elucidation of their functions in specific tissues. The role of some subunits in human disease, however, has not been fully established, and their functions remain uncertain.

Objective: We aimed to expand the range of neurodevelopmental disorders associated with mutations in TRAPP subunits by exome sequencing of consanguineous families.

Methods: Linkage and homozygosity mapping and candidate gene analysis were used to identify homozygous mutations in families. Patient fibroblasts were used to study splicing defect and zebrafish to model the disease.

Results: We identified six individuals from three unrelated families with a founder homozygous splice mutation in TRAPPC6B, encoding a core subunit of the complex TRAPP I. Patients manifested a neurodevelopmental disorder characterised by microcephaly, epilepsy and autistic features, and showed splicing defect. Zebrafish trappc6b morphants replicated the human phenotype, displaying decreased head size and neuronal hyperexcitability, leading to a lower seizure threshold.

Conclusion: This study provides clinical and functional evidence of the role of TRAPPC6B in brain development and function.},
  author       = {Marin Valencia, Isaac and Novarino, Gaia and Johansen, Anide and Rosti, Başak and Issa, Mahmoud and Musaev, Damir and Bhat, Gifty and Scott, Eric and Silhavy, Jennifer and Stanley, Valentina and Rosti, Rasim and Gleeson, Jeremy and Imam, Farhad and Zaki, Maha and Gleeson, Joseph},
  issn         = {0022-2593},
  journal      = {Journal of Medical Genetics},
  number       = {1},
  pages        = {48 -- 54},
  publisher    = {BMJ Publishing Group},
  title        = {{A homozygous founder mutation in TRAPPC6B associates with a neurodevelopmental disorder characterised by microcephaly epilepsy and autistic features}},
  doi          = {10.1136/jmedgenet-2017-104627},
  volume       = {55},
  year         = {2018},
}

@article{3,
  abstract     = {SETD5 gene mutations have been identified as a frequent cause of idiopathic intellectual disability. Here we show that Setd5-haploinsufficient mice present developmental defects such as abnormal brain-to-body weight ratios and neural crest defect-associated phenotypes. Furthermore, Setd5-mutant mice show impairments in cognitive tasks, enhanced long-term potentiation, delayed ontogenetic profile of ultrasonic vocalization, and behavioral inflexibility. Behavioral issues are accompanied by abnormal expression of postsynaptic density proteins previously associated with cognition. Our data additionally indicate that Setd5 regulates RNA polymerase II dynamics and gene transcription via its interaction with the Hdac3 and Paf1 complexes, findings potentially explaining the gene expression defects observed in Setd5-haploinsufficient mice. Our results emphasize the decisive role of Setd5 in a biological pathway found to be disrupted in humans with intellectual disability and autism spectrum disorder.},
  author       = {Deliu, Elena and Arecco, Niccoló and Morandell, Jasmin and Dotter, Christoph and Contreras, Ximena and Girardot, Charles and Käsper, Eva and Kozlova, Alena and Kishi, Kasumi and Chiaradia, Ilaria and Noh, Kyung and Novarino, Gaia},
  journal      = {Nature Neuroscience},
  number       = {12},
  pages        = {1717 -- 1727},
  publisher    = {Nature Publishing Group},
  title        = {{Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition}},
  doi          = {10.1038/s41593-018-0266-2},
  volume       = {21},
  year         = {2018},
}