TY  - JOUR
AU  - Nagy, Vanja
AU  - Hollstein, Ronja
AU  - Pai, Tsung-Pin
AU  - Herde, Michel K
AU  - Buphamalai, Pisanu
AU  - Moeseneder, Paul
AU  - Lenartowicz, Ewelina
AU  - Kavirayani, Anoop
AU  - Korenke, Georg Christoph
AU  - Kozieradzki, Ivona
AU  - Nitsch, Roberto
AU  - Cicvaric, Ana
AU  - Monje Quiroga, Francisco J
AU  - Deardorff, Matthew A
AU  - Bedoukian, Emma C
AU  - Li, Yun
AU  - Yigit, Gökhan
AU  - Menche, Jörg
AU  - Perçin, E Ferda
AU  - Wollnik, Bernd
AU  - Henneberger, Christian
AU  - Kaiser, Frank J
AU  - Penninger, Josef M
TI  - HACE1 deficiency leads to structural and functional neurodevelopmental defects.
JO  - Neurology / Genetics
VL  - 5
IS  - 3
SN  - 2376-7839
CY  - Minneapolis, Minn.
M1  - DZNE-2020-07225
SP  - e330
PY  - 2019
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:31321300
C2  - pmc:PMC6561753
DO  - DOI:10.1212/NXG.0000000000000330
UR  - https://pub.dzne.de/record/140903
ER  -