Mutations in the Tre2/Bub2/Cdc16 (TBC)1 domain family member 24 (TBC1D24) gene 
are associated with a range of inherited neurological disorders, from 
drug-refractory lethal epileptic encephalopathy and DOORS syndrome (deafness, 
onychodystrophy, osteodystrophy, mental retardation, seizures) to non-syndromic 
hearing loss. TBC1D24 has been implicated in neuronal transmission and 
maturation, although the molecular function of the gene and the cause of the 
apparently complex disease spectrum remain unclear. Importantly, heterozygous 
TBC1D24 mutation carriers have also been reported with seizures, suggesting that 
haploinsufficiency for TBC1D24 is significant clinically. Here we have 
systematically investigated an allelic series of disease-associated mutations in 
neurons alongside a new mouse model to investigate the consequences of TBC1D24 
haploinsufficiency to mammalian neurodevelopment and synaptic physiology. The 
cellular studies reveal that disease-causing mutations that disrupt either of 
the conserved protein domains in TBC1D24 are implicated in neuronal development 
and survival and are likely acting as loss-of-function alleles. We then further 
investigated TBC1D24 haploinsufficiency in vivo and demonstrate that TBC1D24 is 
also crucial for normal presynaptic function: genetic disruption of Tbc1d24 
expression in the mouse leads to an impairment of endocytosis and an enlarged 
endosomal compartment in neurons with a decrease in spontaneous 
neurotransmission. These data reveal the essential role for TBC1D24 at the 
mammalian synapse and help to define common synaptic mechanisms that could 
underlie the varied effects of TBC1D24 mutations in neurological disease.