Jutta Gärtner

Georg-August-Universität Göttingen, Göttingen, Lower Saxony, Germany

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Publications (220)908.29 Total impact

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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.
    Journal of Medical Genetics 11/2015; DOI:10.1136/jmedgenet-2015-103232 · 6.34 Impact Factor
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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.
    Clinical Genetics 06/2015; DOI:10.1111/cge.12629 · 3.93 Impact Factor
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    Nature 05/2015; 521(7552):E1-4. DOI:10.1038/nature14444 · 41.46 Impact Factor
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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.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 02/2015; 35(6):2485-91. DOI:10.1523/JNEUROSCI.3246-14.2015 · 6.34 Impact Factor
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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.
    Clinical neuroimaging 01/2015; 7:400-408. DOI:10.1016/j.nicl.2014.06.015 · 2.53 Impact Factor
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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
    Annals of Neurology 01/2015; 77(4). DOI:10.1002/ana.24364 · 9.98 Impact Factor
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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.
    Mitochondrion 01/2015; 21. DOI:10.1016/j.mito.2015.01.001 · 3.25 Impact Factor
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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.
    PLoS ONE 12/2014; 9(12):e115444. DOI:10.1371/journal.pone.0115444 · 3.23 Impact Factor
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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.
    European journal of human genetics: EJHG 11/2014; 23(8). DOI:10.1038/ejhg.2014.250 · 4.35 Impact Factor
  • Article: G.P.188
    E.K.G. Wilichowski · A. Abicht · H. Mayr · R. Horvath · W. Sperl · J. Gärtner ·

    Neuromuscular Disorders 10/2014; 24(9-10):866. DOI:10.1016/j.nmd.2014.06.244 · 2.64 Impact Factor
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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
    eLife Sciences 09/2014; 3. DOI:10.7554/eLife.03640 · 9.32 Impact Factor
  • L. Voges · G. Stettner · D. Weise · K. Brockmann · J. Gärtner · M. Henneke ·

    Neuropediatrics 09/2014; 45(S 01). DOI:10.1055/s-0034-1390657 · 1.24 Impact Factor
  • H. Rosewic · D. Weise · A. Ohlenbusch · J. Gärtner · K. Brockmann ·

    Neuropediatrics 09/2014; 45(S 01). DOI:10.1055/s-0034-1390522 · 1.24 Impact Factor
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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.
    European journal of human genetics: EJHG 08/2014; 23(5). DOI:10.1038/ejhg.2014.160 · 4.35 Impact Factor
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    ABSTRACT: Background: Because of the emergence of novel therapies for multiple sclerosis (MS) and the associated increased risk of progressive multifocal leukoencephalopathy, John Cunningham (JC) virus infection has become a focus of interest for neurologists. However, little is known about JC virus infection in pediatric MS to date. Objective: We aimed to analyze the prevalence of anti-JC virus antibodies, the conversion rate and the influence of the anti-JC virus antibody status on the clinical course in a large pediatric MS cohort. Methods: Anti-JC virus antibodies were analyzed in serum samples within six months of disease onset and during the course of the disease. Clinical data were extracted from a pediatric MS databank. Results: A total of 51.6% of 256 patients were found to be positive for anti-JC virus antibodies at onset of disease. No correlation between antibody status and clinical course was seen. Analyzing 693 follow-up serum samples revealed high titer stability, and an annual conversion rate of 4.37% was seen. Conclusion: No evidence was found that seropositivity for anti-JC virus antibodies influences the clinical course. Surprisingly, seroprevalence for anti-JC virus antibodies was more than twice as high as anticipated in this age group, raising the question of whether the infection increases the risk of MS development.
    Multiple Sclerosis 07/2014; 21(4). DOI:10.1177/1352458514543340 · 4.82 Impact Factor

  • Neurology 07/2014; 83(9). DOI:10.1212/WNL.0000000000000735 · 8.29 Impact Factor
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    ABSTRACT: Mutations in the ATP1A3 gene are associated with rapid-onset dystonia-parkinsonism (RDP) and alternating hemiplegia of childhood (AHC) as well as RDP/AHC intermediate presentations. Phenotypic diversity is being recognized. In order to identify ATP1A3-related phenotypes not meeting the classical criteria for RDP or AHC we lowered the threshold for mutation analysis in clinical presentations resembling AHC or RDP. A novel heterozygous ATP1A3 missense mutation c.2600G > A (p.Gly867Asp, G867D) was detected in a 15-year-old girl. Her clinical phenotype is partially consistent with an intermediate presentation between alternating hemiplegia of childhood and rapid-onset dystonia-parkinsonism and comprises additional yet unreported features. With onset at 4½ years of age recurrent paroxysmal flaccid hemiplegia alternating in laterality was triggered by watching television or playing computer games. Occlusion of both eyes reliably stopped the plegic attacks with the patient remaining awake. Our observation further widens the phenotypic spectrum associated with ATP1A3 mutations.
    Journal of the neurological sciences 06/2014; 341(1-2). DOI:10.1016/j.jns.2014.03.034 · 2.47 Impact Factor
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    ABSTRACT: Mucopolysaccharidosis type IIIA (Sanfilippo A syndrome), a fatal childhood-onset neurodegenerative disease with mild facial, visceral and skeletal abnormalities, is caused by an inherited deficiency of the enzyme N-sulfoglucosamine sulfohydrolase (SGSH; sulfamidase). More than 100 mutations in the SGSH gene have been found to reduce or eliminate its enzymatic activity. However, the molecular understanding of the effect of these mutations has been confined by a lack of structural data for this enzyme. Here, the crystal structure of glycosylated SGSH is presented at 2 Å resolution. Despite the low sequence identity between this unique N-sulfatase and the group of O-sulfatases, they share a similar overall fold and active-site architecture, including a catalytic formylglycine, a divalent metal-binding site and a sulfate-binding site. However, a highly conserved lysine in O-sulfatases is replaced in SGSH by an arginine (Arg282) that is positioned to bind the N-linked sulfate substrate. The structure also provides insight into the diverse effects of pathogenic mutations on SGSH function in mucopolysaccharidosis type IIIA and convincing evidence for the molecular consequences of many missense mutations. Further, the molecular characterization of SGSH mutations will lay the groundwork for the development of structure-based drug design for this devastating neurodegenerative disorder.
    Acta Crystallographica Section D Biological Crystallography 05/2014; 70(Pt 5):1321-35. DOI:10.1107/S1399004714002739 · 2.67 Impact Factor
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    ABSTRACT: Peroxisomes are ubiquitous and dynamic organelles that house many important pathways of cellular metabolism. In recent years it has been demonstrated that mitochondria are tightly connected with peroxisomes and are defective in several peroxisomal diseases. Indeed, these two organelles share metabolic routes as well as resident proteins and, at least in mammals, are connected via a vesicular transport pathway. However the exact extent of cross-talk between peroxisomes and mitochondria remains unclear. Here we used a combination of high throughput genetic manipulations of yeast libraries alongside high content screens to systematically unravel proteins that affect the transport of peroxisomal proteins and peroxisome biogenesis. Follow up work on the effector proteins that were identified revealed that peroxisomes are not randomly distributed in cells but are rather localized to specific mitochondrial subdomains such as mitochondria-ER junctions and sites of acetyl-CoA synthesis. Our approach highlights the intricate geography of the cell and suggests an additional layer of organization as a possible way to enable efficient metabolism. Our findings pave the way for further studying the machinery aligning mitochondria and peroxisomes, the role of the juxtaposition, as well as its regulation during various metabolic conditions. More broadly, the approaches used here can be easily applied to study any organelle of choice, facilitating the discovery of new aspects in cell biology.
    Molecular BioSystems 04/2014; 10(7). DOI:10.1039/c4mb00001c · 3.21 Impact Factor
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    ABSTRACT: We aimed to delineate the clinical and genetic spectrum of ATP1A3-related disorders and recognition of a potential genotype-phenotype correlation. We identified 16 new patients with alternating hemiplegia of childhood (AHC) and 3 new patients with rapid-onset dystonia-parkinsonism (RDP) and included these as well as the clinical and molecular findings of all previously reported 164 patients with mutation-positive AHC and RDP in our analyses. Major clinical characteristics shared in common by AHC and RDP comprise a strikingly asymmetric, predominantly dystonic movement disorder with rostrocaudal gradient of involvement and physical, emotional, or chemical stressors as triggers. The clinical courses include an early-onset polyphasic for AHC, a later-onset mono- or biphasic for RDP, as well as intermediate forms. Meta-analysis of the 8 novel and 38 published ATP1A3 mutations shows that the ones affecting transmembrane and functional domains tend to be associated with AHC as the more severe phenotype. The majority of mutations are located in exons 8, 14, 17, and 18. AHC and RDP constitute clinical prototypes in a continuous phenotypic spectrum of ATP1A3-related disorders. Intermediate phenotypes combining criteria of both conditions are increasingly recognized. Efficient stepwise mutation analysis of the ATP1A3 gene may prioritize those exons where current state of knowledge indicates mutational clusters.
    Neurology 02/2014; 82(11). DOI:10.1212/WNL.0000000000000212 · 8.29 Impact Factor

Publication Stats

3k Citations
908.29 Total Impact Points


  • 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
  • 2013
    • Hebrew University of Jerusalem
      Yerushalayim, Jerusalem, Israel
  • 2012-2013
    • Universitätsklinikum Freiburg
      Freiburg an der Elbe, Lower Saxony, Germany
    • University of Innsbruck
      Innsbruck, Tyrol, Austria
  • 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