biostudies-literatureYang RGeorge Barth Geller ProfessorshipNICHD NIH HHSNCATS NIH HHSHoward Hughes Medical InstituteNIMH NIH HHSOffice of Extramural Research, National Institutes of HealthNINDS NIH HHS19717-19726https://www.ebi.ac.uk/biostudies/studies/S-EPMC6765234biostudies-literatureUnknown116(39)Giant ankyrin-G (gAnkG) coordinates assembly of axon initial segments (AISs), which are sites of action potential generation located in proximal axons of most vertebrate neurons. Here, we identify a mechanism required for normal neural development in humans that ensures ordered recruitment of gAnkG and β4-spectrin to the AIS. We identified 3 human neurodevelopmental missense mutations located in the neurospecific domain of gAnkG that prevent recruitment of β4-spectrin, resulting in a lower density and more elongated pattern for gAnkG and its partners than in the mature AIS. We found that these mutations inhibit transition of gAnkG from a closed configuration with close apposition of N- and C-terminal domains to an extended state that is required for binding and recruitment of β4-spectrin, Proceedings of the National Academy of Sciences of the United States of AmericaNeurodevelopmental mutation of giant ankyrin-G disrupts a core mechanism for axon initial segment assembly.PMC6765234F31NS096848not applicableR21 MH115155F31 NS096848R01 MH098114UL1 TR001863R21 HD087795R01 MH117289R21 MH104316R21MH115155Fernandez-Jaen AWalder-Christensen KKGarcia-Prieto IDLalani SYang RSpeltz LBennett VJiang YHYan HAlvarez SfalseNeurodevelopmental mutation of giant ankyrin-G disrupts a core mechanism for axon initial segment assembly.Giant ankyrin-G (gAnkG) coordinates assembly of axon initial segments (AISs), which are sites of action potential generation located in proximal axons of most vertebrate neurons. Here, we identify a mechanism required for normal neural development in humans that ensures ordered recruitment of gAnkG and β4-spectrin to the AIS. We identified 3 human neurodevelopmental missense mutations located in the neurospecific domain of gAnkG that prevent recruitment of β4-spectrin, resulting in a lower density and more elongated pattern for gAnkG and its partners than in the mature AIS. We found that these mutations inhibit transition of gAnkG from a closed configuration with close apposition of N- and C-terminal domains to an extended state that is required for binding and recruitment of β4-spectrin, 2019-01-01T00:00:00Z2019 Sep2026-05-07T05:52:17.962Z2019-10-11T07:12:33ZS-EPMC67652343145163610.1073/pnas.1909989116