Elucidation of the pathogenesis of Dandy-Walker malformation
Final Report Abstract
Dandy-Walker malformation (DWM) is one of the most common cerebellar malformations in humans. The causes of DWM as well as the mechanisms leading to this malformation are currently not well understood. The Gleeson lab has identified loss-of-function mutations in SOLH in patients with DWM and cloaca. This combination of phenotypes is very rare, and SOLH mutations do not seem to be common in patients with DWM and genitourinary malformations in general. We have generated Solh knockout mice using CRISPR/CAS9, which are viable, fertile and without any discernible phenotypes. SOLH seems to be dispensable for mouse development and survival. In contrast, I found a striking hindbrain phenotype in zebrafish upon morpholino-mediated knockdown of solh. Embryos show strong reduction of neuronal cells during development particularly at the mid/hindbrain boundary. My data also suggest that cell death may be a contributor to the pathology at least in fish. My studies showed that SOLH has protease activity in vitro. Whether this is also true in vivo remains to be determined. Furthermore, potential cleavage targets have yet to be identified. My efforts in identifying SOLH interaction partners using an SOLH overexpression system have remained inconclusive so far, and need to be validated on endogenous levels. In total, this study has identified SOLH loss as a cause for Dandy- Walker malformation in humans and validated its role in hindbrain development using zebrafish as a model system. The mechanisms underlying this disease have yet to be elucidated. One may speculate that SOLH protease function is important in cleavage of certain target proteins relevant to cerebellar development. To identify those potential targets and to validate this hypothesis will be an open question for future studies.
Publications
- (2015). “Dandy-Walker malformation, genitourinary abnormalities, and intellectual disability in two families.” Am J Med Genet A 167A: 2503-2507
Zaki MS, Masri A, Gregor A, Gleeson JG, Rosti RO
(See online at https://doi.org/10.1002/ajmg.a.37225)
