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.
| Original language | English |
|---|---|
| Article number | e330 |
| Journal | Neurology: Genetics |
| Volume | 5 |
| Issue number | 3 |
| Pages (from-to) | e330 |
| ISSN | 2376-7839 |
| DOIs | |
| Publication status | Published - 01.06.2019 |
Funding
From the 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. The authors thank patients and their families for their participation; members of the IMP Biooptics facility for their technical advice and assistance; Dr. David Keays, IMP, Vienna, for the use of behavioral equipment, and members of his team for helpful discussions. In addition, the authors thank Dr. Daniel Lin from Sunjin Lab for the technical support with 3D Images of dendritic spines. The work was supported by the Human Frontiers Science Program (HFSP, to C.H.), the German Research Foundation (DFG, SPP1757, SFB1089 to C.H.), FWF Lise Meitner Postdoctoral Fellowship to V.N., and EMBO Long-Term Fellowship to T.-P.P. F.J.K. is supported by the German Research Foundation (DFG) Research Unit 2488, 'ProtectMove’. J.M.P. is supported by The Austrian Academy of Sciences, the European Community’s Seventh Framework Programme/Advanced ERC grant, and Era of Hope/DOD Excellence grant. V. Nagy has received government research funding from the Austrian Science Fund and the Lise Meitner Postdoctoral Fellowship; and has received foundation/society research support from the Ludwig Boltzmann Society. R. Hollstein, T.-P. Pai, M.K. Herde, P. Buphamalai, and P. Moeseneder report no disclosures. E. Lenartowicz has received foundation/ society research support from the Ludwig Boltzmann Society. Anoop Kavirayani is employed with VBCFs, which receives government funding from the Austrian Federal Ministry of Education, Science, and Research and the City of Vienna. G. Christoph Korenke, I. Kozieradzki, R. Nitsch, A. Cicvaric, F.J. Monje Quiroga, M.A. Deardorff, E.C. Bedoukian, Y. Li, and G. Yigit report no disclosures. Jörg Menche has received government research support from the Vienna Science and Technology Fund. E. Ferda Perçin and B. Wollnik report no disclosures. Christian Henneberger has served on the editorial board for Frontiers in Molecular Neuroscience and Brain Research Bulletin; has received government research support from NRW-Rückkehrerprogramm; and has received foundation/society research support from the Human Frontiers Science Program. F.J. Kaiser has received government research support from the German Research Foundation. J.M. Penninger reports no disclosures. Go to Neurology.org/NG for full disclosures.
Research Areas and Centers
- Research Area: Medical Genetics
