Autophagy is required for the homeostasis of cellular material and is proposed to
be involved in many aspects of health. Defects in the autophagy pathway have been
observed in neurodegenerative disorders; however, no genetically-inherited pathogenic
mutations in any of the core autophagy-related (ATG) genes have been reported in human
patients to date. We identified a homozygous missense mutation, changing a conserved
amino acid, in ATG5 in two siblings with congenital ataxia, mental retardation, and
developmental delay. The subjects' cells display a decrease in autophagy flux and
defects in conjugation of ATG12 to ATG5. The homologous mutation in yeast demonstrates
a 30-50% reduction of induced autophagy. Flies in which Atg5 is substituted with the
mutant human ATG5 exhibit severe movement disorder, in contrast to flies expressing
the wild-type human protein. Our results demonstrate the critical role of autophagy
in preventing neurological diseases and maintaining neuronal health.
