Animal models are required to characterize the contribution of candidate genes to patients’ phenotypes

Neurodevelopmental disorders have in common that they have a negative effect on cognitive abilities and executive functions of patients. Based on the complexity of these functions, it is not surprising that many genes involved in different steps of neural circuit formation and function are associated with disease development. Monogenetic forms of neurodevelopmental disorders are the exception rather than the rule. However, monogenetic disorders are easier to study in animal models.

Using chicken embryos as a model, we demonstrated a direct role of a gene on human chromosome 5 (C5ORF42) also known as Jbts17 or CPLANE1 in neural circuit formation. This gene was identified as the cause of a subgroup of Joubert syndrome, OFD-VI (oro-facial-digital syndrome type VI). However, it was not clear whether the mutation abolishing gene function was directly responsible and sufficient for the phenotypes seen in patients.
Current and future studies aim at understanding the molecular mechanisms of C5ORF42/Jbts17 in neural circuit formation and the migration of neural crest cells that contribute to craniofacial development. Along the same lines, we generate and validate animal models for human neurodevelopmental disorders that in turn will allow us to characterize disease mechanisms in the context of candidate genes identified by exome or whole genome sequencing of patient DNA.

Key Publications

Asadollahi R, Strauss JE, Zenker M, Beuing O, Edvardson S, Elpeleg O, Strom TM, Joset P, Niedrist D, Otte C, Oneda B, Boonsawat P, Azzarello-Burri S, Bartholdi D, Papik M, Zweier M, Haas C, Ekici AB, Baumer A, Boltshauser E, Steindl K, Nothnagel M, Schinzel A, Stoeckli ET, and Rauch A. (2018) Clinical and experimental evidence suggest a link between KIF7 and C5orf42-related ciliopathies through Sonic Hedgehog signaling.
Eur J Hum Genet. 26:197-209. doi: 10.1038/s41431-017-0019-9.