HACE1 deficiency leads to structural and functional neurodevelopmental defects
| Autor: | Frank J. Kaiser, Emma Bedoukian, Roberto Nitsch, Georg Christoph Korenke, Bernd Wollnik, Michel K. Herde, Josef M. Penninger, Yun Li, Anoop Kavirayani, Ana Cicvaric, Ronja Hollstein, Paul Moeseneder, Christian Henneberger, Ewelina Lenartowicz, Gökhan Yigit, Vanja Nagy, Tsung-Pin Pai, Matthew A. Deardorff, Francisco Quiroga, E. Ferda Percin, Pisanu Buphamalai, Jörg Menche, Ivona Kozieradzki |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Hippocampus Biology medicine.disease_cause Article Synapse 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Internal medicine medicine ddc:610 Genetics (clinical) Exome sequencing Mutation Psychomotor retardation Long-term potentiation Phenotype 030104 developmental biology Endocrinology Neurology (clinical) neurodevelopmental defects HACE1 medicine.symptom 030217 neurology & neurosurgery |
| Zdroj: | Neurology / Genetics 5(3), e330 (2019). doi:10.1212/NXG.0000000000000330 Neurology: Genetics |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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