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@ARTICLE{Nagy:140903,
      author       = {Nagy, Vanja and Hollstein, Ronja and Pai, Tsung-Pin and
                      Herde, Michel K and Buphamalai, Pisanu and Moeseneder, Paul
                      and Lenartowicz, Ewelina and Kavirayani, Anoop and Korenke,
                      Georg Christoph and Kozieradzki, Ivona and Nitsch, Roberto
                      and Cicvaric, Ana and Monje Quiroga, Francisco J and
                      Deardorff, Matthew A and Bedoukian, Emma C and Li, Yun and
                      Yigit, Gökhan and Menche, Jörg and Perçin, E Ferda and
                      Wollnik, Bernd and Henneberger, Christian and Kaiser, Frank
                      J and Penninger, Josef M},
      title        = {{HACE}1 deficiency leads to structural and functional
                      neurodevelopmental defects.},
      journal      = {Neurology / Genetics},
      volume       = {5},
      number       = {3},
      issn         = {2376-7839},
      address      = {Minneapolis, Minn.},
      reportid     = {DZNE-2020-07225},
      pages        = {e330},
      year         = {2019},
      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.},
      cin          = {U Preclinical Researchers - Bonn},
      ddc          = {610},
      cid          = {I:(DE-2719)7000005},
      pnm          = {342 - Disease Mechanisms and Model Systems (POF3-342)},
      pid          = {G:(DE-HGF)POF3-342},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:31321300},
      pmc          = {pmc:PMC6561753},
      doi          = {10.1212/NXG.0000000000000330},
      url          = {https://pub.dzne.de/record/140903},
}