ABSTRACT
OBJECTIVE:
We aim to characterize the
causality and molecular and functional underpinnings of HACE1
deficiency in a
mouse model of a recessive neurodevelopmental
syndrome called
spastic paraplegia and psychomotor retardation with or without seizures (SPPRS).
METHODS:
By
exome sequencing, we identified 2 novel homozygous truncating
mutations in HACE1 in 3
patients from 2
families, p.Q209* and p.R332*. Furthermore, we performed detailed molecular and phenotypic analyses of Hace1 knock-out (KO)
mice and SPPRS
patient fibroblasts.
RESULTS:
We show that Hace1 KO
mice display many clinical features of SPPRS including enlarged ventricles, hypoplastic
corpus callosum, as well as
locomotion and
learning deficiencies. Mechanistically, loss of HACE1 results in altered levels and activity of the small
guanosine triphosphate (
GTP)ase, RAC1. In addition, HACE1
deficiency results in reduction in synaptic puncta number and
long-term potentiation in the
hippocampus. Similarly, in SPPRS
patient-derived
fibroblasts,
carrying a disruptive HACE1
mutation resembling loss of HACE1 in KO
mice, we observed marked
upregulation of the total and active,
GTP-bound, form of RAC1, along with an induction of RAC1-regulated
downstream pathways.
CONCLUSIONS:
Our results provide a first
animal model to dissect this complex
human disease syndrome, establishing the first causal proof that a HACE1
deficiency results in decreased
synapse number and structural and behavioral neuropathologic features that resemble SPPRS
patients.