Jutta Gärtner

Universitätsklinikum Freiburg, Freiburg an der Elbe, Lower Saxony, Germany

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Publications (232)969.35 Total impact

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    ABSTRACT: The targeting signals and mechanisms of soluble peroxisomal proteins are well understood, whereas less is known about the signals and targeting routes of peroxisomal membrane proteins (PMP). Pex15 and PEX26, tail-anchored proteins in yeast and mammals, respectively, exert a similar cellular function in the recruitment of AAA peroxins at the peroxisomal membrane. But despite their common role, Pex15 and PEX26 are neither homologs nor they are known to follow similar targeting principles. Here we show that Pex15 targets to peroxisomes in mammalian cells, and PEX26 reaches peroxisomes when expressed in yeast cells. In both proteins C-terminal targeting information is sufficient for correct sorting to the peroxisomal membrane. In yeast, PEX26 follows the pathway that also ensures correct targeting of Pex15: PEX26 enters the endoplasmic reticulum (ER) in a GET-dependent and Pex19-independent manner. Like in yeast, PEX26 enters the ER in mammalian cells, however, independently of GET/TRC40. These data show that conserved targeting information is employed in yeast and higher eukaryotes during the biogenesis of peroxisomal tail-anchored proteins.
    Full-text · Article · Dec 2015 · Scientific Reports
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    ABSTRACT: Background: Leukodystrophies are genetic white matter disorders affecting the formation or maintenance of myelin. Among the recently discovered genetic defects associated with leukodystrophies, several genes converge on a common mechanism involving protein transcription/translation and ER stress response. Methods: The genetic basis of a novel congenital leukodystrophy, associated with early onset spastic paraparesis, acquired microcephaly and optic atrophy was studied in six patients from three unrelated Ashkenazi-Jewish families. To this end we used homozygosity mapping, exome analysis, western blot (Hikeshi, HSF1-pS326 and b-actin) in patient fibroblasts, indirect immunofluorescence (HSP70 and HSF1) in patient fibroblasts undergoing heat shock stress, nuclear injection of plasmids expressing Hikeshi or EGFP in patient fibroblasts, in situ hybridization and Immunoblot analysis of Hikeshi in newborn and adult mouse brain. Results: All the patients were homozygous for a missense mutation, p.Val54Leu, in C11ORF73 encoding HSP70 nuclear transporter protein, Hikeshi. The mutation segregated with the disease in the families and was carried by 1:200 Ashkenazi-Jewish individuals. The mutation was associated with undetectable level of Hikeshi in the patients' fibroblasts and with lack of nuclear HSP70 during heat shock stress, a phenomenon which was reversed upon the introduction of normal human Hikeshi to the patients cells. Hikeshi was found to be expressed in central white matter of mouse brain. Conclusions: These data underscore the importance of Hikeshi for HSP70 relocation into the nucleus. It is likely that in the absence of Hikeshi, HSP70 cannot attenuate the multiple heat shock induced nuclear phenotypes, leaving the cells unprotected during heat shock stress. We speculate that the sudden death of three of the six patients following a short febrile illness and the life-threatening myo-pericarditis in the fourth are the result of excess extra-nuclear HSP70 level which initiates cytokine release or provide target for natural killer cells. Alternatively, nuclear HSP70 might play an active role in stressed cells protection.
    No preview · Article · Nov 2015 · Journal of Medical Genetics
  • H.-M. Hummel · J. Gärtner · P. Huppke
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    ABSTRACT: Multiple sclerosis is a chronic inflammatory disease of the central nervous system, increasingly diagnosed in children and adolescents. This article gives an overview of the characteristics of pediatric multiple sclerosis and will focus on the diagnostic criteria and the specific pediatric differential diagnoses as well as the current treatment recommendations.
    No preview · Article · Aug 2015 · Padiatrische Praxis
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    ABSTRACT: Recent progress in genetic testing has facilitated obtaining an etiologic diagnosis in children with developmental delay/intellectual disability (DD/ID) or multiple congenital anomalies (MCA) or both. Little is known about the benefits of diagnostic elucidation for affected families. We studied the impact of a genetic diagnosis on parental quality of life (QoL) using a validated semiquantitative questionnaire in families with a disabled child investigated by array CGH. We received completed questionnaires from 95 mothers and 76 fathers of 99 families. We used multivariate analysis for adjustment of potential confounders. Taken all 99 families together maternal QoL score (percentile rank scale 51.05) was significantly lower than fathers' QoL (61.83, p = 0.01). Maternal QoL score was 20.17 (95% CI [5.49; 34.82]) percentile rank scales higher in mothers of children with diagnostic (n = 34) array CGH as opposed to mothers of children with inconclusive (n = 65) array CGH (Hedges' g 0,71). Comparison of these QoL scores with retrospectively recalled QoL before array CGH revealed an increase of maternal QoL after diagnostic clarification. Our results indicate a benefit for maternal QoL if a genetic test, here array CGH, succeeds to clarify the etiologic diagnosis in a disabled child. This article is protected by copyright. All rights reserved.
    No preview · Article · Jun 2015 · Clinical Genetics
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    Full-text · Article · May 2015 · Nature
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    Full-text · Article · May 2015 · Nature

  • No preview · Article · May 2015 · European Journal of Paediatric Neurology
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    ABSTRACT: The mechanisms behind CSF flow in humans are still not fully known. CSF circulates from its primary production sites at the choroid plexus through the brain ventricles to reach the outer surface of the brain in the subarachnoid spaces from where it drains into venous bloodstream and cervical lymphatics. According to a recent concept of brain fluid transport, established in rodents, CSF from the brain surface also enters the brain tissue along para-arterial routes and exits through paravenous spaces again into subarachnoid compartments. This unidirectional flow is mainly driven by arterial pulsation. To investigate how CSF flow is regulated in humans, we applied a novel real-time magnetic resonance imaging technique at high spatial (0.75 mm) and temporal (50 ms) resolution in healthy human subjects. We observed significant CSF flow exclusively with inspiration. In particular, during forced breathing, high CSF flow was elicited during every inspiration, whereas breath holding suppressed it. Only a minor flow component could be ascribed to cardiac pulsation. The present results unambiguously identify inspiration as the most important driving force for CSF flow in humans. Inspiratory thoracic pressure reduction is expected to directly modulate the hydrostatic pressure conditions for the low-resistance paravenous, venous, and lymphatic clearance routes of CSF. Furthermore, the experimental approach opens new clinical opportunities to study the pathophysiology of various forms of hydrocephalus and to design therapeutic strategies in relation to CSF flow alterations. Copyright © 2015 the authors 0270-6474/15/352485-07$15.00/0.
    Full-text · Article · Feb 2015 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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    ABSTRACT: Currently, it is unclear whether pediatric multiple sclerosis (PMS) is a pathoetiologically homogeneous disease phenotype due to clinical and epidemiological differences between early and late onset PMS (EOPMS and LOPMS). Consequently, the question was raised whether diagnostic guidelines need to be complemented by spe-cific EOPMS markers. To search for such markers, we analyzed cerebral MRI images acquired with standard pro-tocols using computer-based classification techniques. Specifically, we applied classification algorithms to gray (GM) and white matter (WM) tissue probability parameters of small brain regions derived from T2-weighted MRI images of EOPMS patients (onset b12 years), LOPMS patients (onset ≥12 years), and healthy controls (HC). This was done for PMS subgroups matched for disease duration and participant age independently. As ex-pected, maximal diagnostic information for distinguishing PMS patients and HC was found in a periventricular WM area containing lesions (87.1% accuracy, p b 2.2 × 10 −5). MRI-based biomarkers specific for EOPMS were identified in prefrontal cortex. Specifically, a coordinate in middle frontal gyrus contained maximal diagnostic in-formation (77.3%, p = 1.8 × 10 −4). Taken together, we were able to identify biomarkers reflecting pathognomon-ic processes specific for MS patients with very early onset. Especially GM involvement in the separation between PMS subgroups suggests that conventional MRI contains a richer set of diagnostically informative features than previously assumed.
    Full-text · Article · Jan 2015 · Clinical neuroimaging
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    ABSTRACT: Objective Axonal damage occurs early in multiple sclerosis (MS) and contributes to the degree of clinical disability. Children with MS more often show disabling and polyfocal neurological symptoms at disease onset than adults with MS. Thus, axonal damage may differ between pediatric and adult MS patients.Methods We analyzed axonal pathology in archival brain biopsy and autopsy samples from 19 children with early MS. Lesions were classified according to demyelinating activity and presence of remyelination. Axonal density and extent of acute axonal damage were assessed using Bielschowsky silver impregnation and immunohistochemistry for amyloid precursor protein (APP), respectively. Axonal injury was correlated with the inflammatory infiltrate as well as clinical characteristics. Results were compared with data from adult MS patients.ResultsAcute axonal damage was most extensive in early active demyelinating (EA) lesions of pediatric patients and correlated positively with the Expanded Disability Status Scale at attack leading to biopsy/autopsy. Comparison with 12 adult patients showed a 50% increase in the extent of acute axonal damage in EA lesions from children compared to adults, with the highest number of APP-positive spheroids found prior to puberty. The extent of acute axonal damage correlated positively with the number of lesional macrophages. Axonal density was reduced in pediatric lesions irrespective of the demyelinating activity or the presence of remyelination. Axonal reduction was similar between children and adults.InterpretationOur results provide evidence for more pronounced acute axonal damage in inflammatory demyelinating lesions from children compared to adults. Ann Neurol 2015;77:655–667
    No preview · Article · Jan 2015 · Annals of Neurology
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    ABSTRACT: The apoptosis-inducing factor (AIF) functions as a FAD-dependent NADH oxidase in mitochondria. Upon apoptotic stimulation it is released from mitochondria and migrates to the nucleus where it induces chromatin condensation and DNA fragmentation. So far mutations in AIFM1, a X-chromosomal gene coding for AIF, have been described in three families with 11 affected males. We report here on a further patient thereby expanding the clinical and mutation spectrum. In addition, we review the known phenotypes related to AIFM1 mutations. The clinical course in the male patient described here was characterized by phases with rapid deterioration and long phases without obvious progression of disease. At age 2.5 years he developed hearing loss and severe ataxia and at age 10 years muscle wasting, swallowing difficulties, respiratory insufficiency and external opthamoplegia. By next generation sequencing of whole exome we identified a hemizygous missense mutation in the AIFM1 gene, c.727G > T (p.Val243Leu) affecting a highly conserved residue in the FAD-binding domain. Summarizing what is known today, mutations in AIFM1 are associated with a progressive disorder with myopathy, ataxia and neuropathy. Severity varies greatly even within one family with onset of symptoms between birth and adolescence. 3 of 12 patients died before age 5 years while others were still able to walk during young adulthood. Less frequent symptoms were hearing loss, seizures and psychomotor regression. Results from clinical chemistry, brain imaging and muscle biopsy were unspecific and inconsistent.
    No preview · Article · Jan 2015 · Mitochondrion
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    ABSTRACT: Rett syndrome, one of the most common causes of mental retardation in females, is caused by mutations in the X chromosomal gene MECP2. Mice deficient for MeCP2 recapitulate some of the symptoms seen in patients with Rett syndrome. It has been shown that reactivation of silent MECP2 alleles can reverse some of the symptoms in these mice. We have generated a knockin mouse model for translational research that carries the most common nonsense mutation in Rett syndrome, R168X. In this article we describe the phenotype of this mouse model. In male MeCP2R168X mice life span was reduced to 12-14 weeks and bodyweight was significantly lower than in wild type littermates. First symptoms including tremor, hind limb clasping and inactivity occurred at age 27 days. At age 6 weeks nest building, rotarod, open-field and elevated plus maze experiments showed impaired motor performance, reduced activity and decreased anxiety-like behavior. Plethysmography at the same time showed apneas and irregular breathing with reduced frequency. Female MeCP2R168X mice showed no significant abnormalities except decreased performance on the rotarod at age 9 months. In conclusion we show that the male MeCP2R168X mice have a phenotype similar to that seen in MECP2 knockout mouse models and are therefore well suited for translational research. The female mice, however, have a much milder and less constant phenotype making such research with this mouse model more challenging.
    Full-text · Article · Dec 2014 · PLoS ONE
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    ABSTRACT: The European Journal of Human Genetics is the official Journal of the European Society of Human Genetics, publishing high-quality, original research papers, short reports, News and Commentary articles and reviews in the rapidly expanding field of human genetics and genomics.
    No preview · Article · Nov 2014 · European journal of human genetics: EJHG
  • Article: G.P.188

    No preview · Article · Oct 2014 · Neuromuscular Disorders
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    ABSTRACT: Translational readthrough gives rise to low abundance proteins with C-terminal extensions beyond the stop codon. To identify functional translational readthrough, we estimated the readthrough propensity (RTP) of all stop codon contexts of the human genome by a new regression model in silico, identified a nucleotide consensus motif for high RTP by using this model, and analyzed all readthrough extensions in silico with a new predictor for peroxisomal targeting signal type 1 (PTS1). Lactate dehydrogenase B (LDHB) showed the highest combined RTP and PTS1 probability. Experimentally we show that at least 1.6% of the total cellular LDHB is targeted to the peroxisome by a conserved hidden PTS1. The readthrough-extended lactate dehydrogenase subunit LDHBx can also co-import LDHA, the other LDH subunit, into peroxisomes. Peroxisomal LDH is conserved in mammals and likely contributes to redox equivalent regeneration in peroxisomes. DOI: http://dx.doi.org/10.7554/eLife.03640.001
    Full-text · Article · Sep 2014 · eLife Sciences
  • H. Rosewic · D. Weise · A. Ohlenbusch · J. Gärtner · K. Brockmann

    No preview · Article · Sep 2014 · Neuropediatrics

  • No preview · Article · Sep 2014 · Neuropediatrics

  • No preview · Article · Sep 2014 · Neuropediatrics
  • L. Voges · G. Stettner · D. Weise · K. Brockmann · J. Gärtner · M. Henneke

    No preview · Article · Sep 2014 · Neuropediatrics
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    ABSTRACT: So far very few patients with sequence variants in the closely related tectonic genes TCTN1-3 have been described. By multi-gene panel next-generation sequencing (NGS) in patients with Joubert syndrome, we identified two more patients and summarize what is currently known about the phenotypes associated with sequence variants in these genes. In a boy aged 12 years with intellectual disability and the classical molar tooth sign on MRI, a homozygous splice-site sequence variant in TCTN3 leading to in-frame skipping of exon 7 was detected. A previously described non-truncating sequence variant in TCTN3 was also associated with Joubert syndrome, whereas four truncating sequence variants were detected in patients with Meckel-Gruber or Mohr-Majewski syndrome. The second patient, a boy aged 7 years with severe psychomotor retardation, was found to carry a homozygous canonic splice-site sequence variant in TCTN2. So far, only three sequence variants associated with Joubert syndrome and two with Meckel-Gruber syndrome have been described in this gene. Reviewing the clinical data on patients with sequence variants in the tectonic genes TCTN1-3 reveals that all of them have a neurological phenotype with vermis hypoplasia or occipital encephalocele associated with severe intellectual disability in the surviving patients. In contrast, other features frequently seen in patients with ciliopathies such as nephronophthisis, liver fibrosis, retinal dystrophy or coloboma have not been reported. Our patients emphasize the usefulness and efficacy of a comprehensive NGS panel approach. A concise genetic diagnosis may help to prevent unnecessary investigations and improve the clinical management of these patients.European Journal of Human Genetics advance online publication, 13 August 2014; doi:10.1038/ejhg.2014.160.
    No preview · Article · Aug 2014 · European journal of human genetics: EJHG

Publication Stats

4k Citations
969.35 Total Impact Points

Institutions

  • 2012-2015
    • Universitätsklinikum Freiburg
      Freiburg an der Elbe, Lower Saxony, Germany
    • University of Innsbruck
      Innsbruck, Tyrol, Austria
  • 2003-2015
    • Georg-August-Universität Göttingen
      • • Faculty of Medicine
      • • Department of Plant Biochemistry
      Göttingen, Lower Saxony, Germany
  • 2006-2014
    • Universitätsmedizin Göttingen
      • Division of Neuropediatrics
      Göttingen, Lower Saxony, Germany
    • Zentrum für Molekulare Neurobiologie Hamburg
      Hamburg, Hamburg, Germany
  • 2013
    • Hebrew University of Jerusalem
      Yerushalayim, Jerusalem, Israel
  • 1994-2003
    • Heinrich-Heine-Universität Düsseldorf
      Düsseldorf, North Rhine-Westphalia, Germany
  • 1997
    • Universitätsklinikum Düsseldorf
      Düsseldorf, North Rhine-Westphalia, Germany
  • 1993
    • Kennedy Krieger Institute
      Baltimore, Maryland, United States
    • Howard Hughes Medical Institute
      Ашбърн, Virginia, United States
  • 1986-1988
    • University of Hamburg
      • Department of Paediatrics
      Hamburg, Hamburg, Germany