Journal Article

DZNE-2020-07225

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png HACE1 deficiency leads to structural and functional neurodevelopmental defects.

Nagy, V. ; Hollstein, R. ; Pai, T.-P. ; Herde, M. K. ; Buphamalai, P. ; Moeseneder, P. ; Lenartowicz, E. ; Kavirayani, A. ; Korenke, G. C. ; Kozieradzki, I. ; Nitsch, R. ; Cicvaric, A. ; Monje Quiroga, F. J. ; Deardorff, M. A. ; Bedoukian, E. C. ; Li, Y. ; Yigit, G. ; Menche, J. ; Perçin, E. F. ; Wollnik, B. ; Henneberger, C.DZNE* ; Kaiser, F. J. ; Penninger, J. M. (Corresponding author)

2019
Minneapolis, Minn.

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Please use a persistent id in citations: doi:10.1212/NXG.0000000000000330

Abstract: We 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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Contributing Institute(s):

1. U Preclinical Researchers - Bonn (U Preclinical Researchers - Bonn)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2019

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Database coverage:
; ; ; ; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; DOAJ Seal ; IF < 5 ; JCR ; SCOPUS ; Web of Science Core Collection

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