Neurol Genet 2019 Jun 29;5(3):e330. Epub 2019 Apr 29.
IMBA (V.N., T.-P.P., P.M., A.K., I.K., R.N., J.M.P.), Institute of Molecular Biotechnology of the Austrian Academy of Sciences, VBC-Vienna BioCenter Campus, Austria; Department of Medical Genetics (J.M.P.), Life Science Institute, University of British Columbia, Vancouver, Canada; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (V.N., E.L.), Vienna, Austria; Section for Functional Genetics at the Institute of Human Genetics (R.H., F.J.K.), University of Lübeck; German Center for Cardiovascular Research (DZHK e.V.) (F.J.K.), Partner Site Hamburg/Kiel/Lübeck, Lübeck; Institute of Cellular Neurosciences (M.K.H., C.H.), University of Bonn Medical School, Germany; Centre for Neuroendocrinology (M.K.H.), Department of Physiology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand; Department of Neurophysiology and Neuropharmacology (A.C., F.J.M.Q.), Center for Physiology and Pharmacology, Medical University of Vienna, Austria; Drug Safety and Metabolism (R.N.), IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden; Division of Genetics and the Roberts Individualized Medical Genetics Center (M.A.D., E.C.B.), Children's Hospital of Philadelphia, PA; Departments of Pediatrics (M.A.D.), University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Institute of Human Genetics (Y.L., G.Y., B.W.), University Medical Center Göttingen, Germany; Institute of Neurology (C.H.), University College London, UK; German Center for Neurodegenerative Diseases (DZNE) (C.H.), Bonn, Germany; Zentrum für Kinder- und Jugendmedizin (G.C.K.), Neuropädiatrie, Klinikum Oldenburg, Germany; Department of Medical Genetics (E.F.P.), Faculty of Medicine, Gazi University, Ankara, Turkey; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences (P.B., J.M.), Vienna, Austria.
Objective: We aim to characterize the causality and molecular and functional underpinnings of 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 in 3 patients from 2 families, p.Q209* and p.R332*. Furthermore, we performed detailed molecular and phenotypic analyses of knock-out (KO) mice and SPPRS patient fibroblasts.
Results: We show that 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 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.