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000140903 037__ $$aDZNE-2020-07225
000140903 041__ $$aEnglish
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000140903 1001_ $$aNagy, Vanja$$b0
000140903 245__ $$aHACE1 deficiency leads to structural and functional neurodevelopmental defects.
000140903 260__ $$aMinneapolis, Minn.$$c2019
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000140903 520__ $$aWe 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).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.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.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.
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000140903 7001_ $$aHollstein, Ronja$$b1
000140903 7001_ $$aPai, Tsung-Pin$$b2
000140903 7001_ $$aHerde, Michel K$$b3
000140903 7001_ $$aBuphamalai, Pisanu$$b4
000140903 7001_ $$aMoeseneder, Paul$$b5
000140903 7001_ $$aLenartowicz, Ewelina$$b6
000140903 7001_ $$aKavirayani, Anoop$$b7
000140903 7001_ $$aKorenke, Georg Christoph$$b8
000140903 7001_ $$aKozieradzki, Ivona$$b9
000140903 7001_ $$aNitsch, Roberto$$b10
000140903 7001_ $$aCicvaric, Ana$$b11
000140903 7001_ $$aMonje Quiroga, Francisco J$$b12
000140903 7001_ $$aDeardorff, Matthew A$$b13
000140903 7001_ $$aBedoukian, Emma C$$b14
000140903 7001_ $$aLi, Yun$$b15
000140903 7001_ $$aYigit, Gökhan$$b16
000140903 7001_ $$aMenche, Jörg$$b17
000140903 7001_ $$aPerçin, E Ferda$$b18
000140903 7001_ $$aWollnik, Bernd$$b19
000140903 7001_ $$0P:(DE-2719)2811625$$aHenneberger, Christian$$b20$$udzne
000140903 7001_ $$aKaiser, Frank J$$b21
000140903 7001_ $$0P:(DE-HGF)0$$aPenninger, Josef M$$b22$$eCorresponding author
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