HACE1 deficiency leads to structural and functional neurodevelopmental defects

Abstract

ObjectiveWe 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).MethodsBy 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.ResultsWe 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.ConclusionsOur 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.

Physiopathological Bases of the Disease Caused by HACE1 Mutations: Alterations in Autophagy, Mitophagy and Oxidative Stress Response

“…The identified mutation was predicted to generate a premature termination codon at residue 80; therefore, the disruptive effect was demonstrated by Western Blot, as HACE1 protein expression levels were absent in patient fibroblasts. HACE1 plays an important role in tagging specific proteins for subcellular localization or proteasomal degradation [1] and, as confirmed here by Western Blot analysis, it is mainly expressed in brain tissues [13,30,31].…”

“…To date HACE1 bi-allelic mutations have been reported in eight unrelated families [10][11][12][13]. The clinical data of the previously described individuals do not differ from the phenotype of the patient reported here, but 3-MGA-uria has not been reported in any of the previous cases.…”

“…Brain abnormalities are also present in some patients and include hypoplastic corpus callosum, cerebral atrophy, delayed myelination and reduced white matter content. Although mutations in HACE1 have been reported in 18 patients from eight unrelated families, the molecular mechanism underlying the pathogenesis of the disease has not been well determined [10][11][12][13]. In fact, a very recent manuscript reported the unique evidence to date about the pathogenic mechanisms underlying this disorder [13].…”

“…Although mutations in HACE1 have been reported in 18 patients from eight unrelated families, the molecular mechanism underlying the pathogenesis of the disease has not been well determined [10][11][12][13]. In fact, a very recent manuscript reported the unique evidence to date about the pathogenic mechanisms underlying this disorder [13]. This research showed that elevated levels of the Ras-related C3 botulinum toxin substrate 1 protein (RAC1), a well-known target of HACE1, were found in HACE1-knockout mice as well as in patient cells, hypothesizing that altered RAC1 signalling might contribute to the pathogenesis of the disorder [13,14].…”

“…In fact, a very recent manuscript reported the unique evidence to date about the pathogenic mechanisms underlying this disorder [13]. This research showed that elevated levels of the Ras-related C3 botulinum toxin substrate 1 protein (RAC1), a well-known target of HACE1, were found in HACE1-knockout mice as well as in patient cells, hypothesizing that altered RAC1 signalling might contribute to the pathogenesis of the disorder [13,14]. The role of RAC1 in the physiopathology of HACE1 deficiency is supported by the fact that this protein is involved in brain development and in the regulation of reactive oxygen species (ROS) levels [6,[15][16][17].…”