Identification and functional characterization of novel monogenic causes for spina bifida

• Applicant: Dr. Caroline Kolvenbach
• Subject Area: Pediatric and Adolescent Medicine ; Human Genetics
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 499462148

Neural tube defects are the most common central nervous system malformation with an incidence of 1 in 1,000 births and the second most common birth defect. They occur between the 3rd and 4th week of gestation when there is incomplete closure of the embryonic neural tube and vertebral arches usually at the caudal or cranial end. Clefts at the caudal end are more common and are referred to as spina bifida (SB). Therapy requires a multidisciplinary team involving pediatricians, nephrologists, urologists, neurologist, (neuro-)surgeons, physiotherapists, orthopedics and psychologists. The etiology of SB is not well understood yet. Previous studies suggested SB to manifest due to a combination of genetic and non-genetic factors. Non-genetic factors may include nutritional factors, such as folic acid deficiency. Several lines of evidence indicate that SB can even be of a monogenetic origin and so far, likely deleterious variants in a few candidate genes have been identified. Here, I want to focus on the analysis of the only recently identified novel candidate genes MTMR8, ATG2B and PIK3R4, all involved in the process of autophagy. They appear to be particularly promising novel candidate genes because previously, mutations have been identified in other genes influencing autophagy in individuals suffering from SB. I want to decipher the functional roles of these three candidate genes. I also plan to study the effect of the identified mutations on autophagy and their role in the pathogenesis of SB, using cell culture experiments as well as a CRISPR/Cas9 approach in zebrafish. I will also screen for novel genes involved in the pathophysiology of the SB in additional exome data available from the Hildebrandt lab. In summary, I expect that my findings will lead to a better understanding of the pathophysiology of SB and eventually its frequent concomitant diseases such as bladder and kidney impairment.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Friedhelm Hildebrandt