Medical Scientist-Programm 2026

Thema: "Pathophysiology of a severe neurodevelopmental disorder caused by FAM126B deficiency"

Zusammenfassung:
Phosphoinositide signaling is essential for membrane identity, vesicular trafficking and growth signaling. The lipid kinase PI4KIIIα (PI4KA) generates phosphatidylinositol 4-phosphate (PI4P) which is a precursor of other PIPs. Defects in the PI4KA complex components cause severe neurodevelopmental disorders, underscoring the developmental importance of this signaling axis. However, the biological function of the PI4KA complex component FAM126B remains poorly understood. Our colleagues from the clinics of neuropediatric identified a homozygous loss-of-function mutation in FAM126B (c.167-170del) in a patient with a severe and fatal neurodevelopmental disorder. Consistent with the patient data, Fam126b knockout mice exhibit early postnatal lethality, and patient-derived brain organoids show marked growth impairment suggesting that FAM126B loss-of-function is disease-causing. We hypothesize that FAM126B is required for proper PI4KA-dependent phosphoinositide signaling and downstream growth pathways during neurodevelopment. To test this hypothesis, we will combine patient-derived and isogenic iPSC brain organoids, proteomic and transcriptomic profiling, mechanistic analysis of PI4K signaling, and in vivo studies with our Fam126b knockout mouse model. This comprehensive, multi-model approach will define the molecular function of FAM126B in neurodevelopment, establish causal disease mechanisms, and uncover fundamental principles of phosphoinositide-dependent signaling relevant to human neurodevelopmental disorders.