David H Gutmann

Washington University in St. Louis, San Luis, Missouri, United States

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Publications (437)2653.12 Total impact

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    Yi-Hsien Chen · Scott M Gianino · David H Gutmann
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    ABSTRACT: Neurofibromatosis type 1 (NF1) is a common neurodevelopmental disorder caused by impaired function of the neurofibromin RAS regulator. Using a combination of Nf1 genetically engineered mice and pharmacological/genetic inhibition approaches, we report that neurofibromin differentially controls neural stem cell (NSC) proliferation and multilineage differentiation through the selective use of the PI3K/AKT and RAF/MEK pathways. While PI3K/AKT governs neurofibromin-regulated NSC proliferation, multilineage differentiation is MEK-dependent. Moreover, whereas MEK-regulated multilineage differentiation requires Smad3-induced Jagged-1 expression and Notch activation, MEK/Smad3-regulated Hes1 induction is only responsible for astrocyte and neuronal differentiation. Collectively, these findings establish distinct roles for the RAS effector pathways in regulating brain NSC function. © 2015 Chen et al.; Published by Cold Spring Harbor Laboratory Press.
    Genes & development 08/2015; 29(16). DOI:10.1101/gad.261677.115 · 10.80 Impact Factor
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    ABSTRACT: To examine the distribution of quantitative autistic traits (QATs) in an independent neurofibromatosis type I (NF1) sample, the relationships between QAT, sex, and attention deficit hyperactivity disorder (ADHD) symptomatology, and to explore evidence for QAT mutational specificity within families. Age-appropriate versions of the Social Responsiveness Scale, second edition and the Conners Adult ADHD Rating Scales were completed for 103 patients with NF1 from the Washington University Neurofibromatosis Center. Patients with NF1 exhibited a pathologically shifted unimodal distribution for QAT. Forty-four percent of the subjects exhibited a QAT burden at or above 1 SD from the population mean; 13% scored at or above the extreme first percentile of the general population distribution. Elevations in ADHD symptomatology exhibited a distinct bimodal distribution; however, mean ADHD index scores were equivalent in patients who had been diagnosed in the community with ADHD compared with those who had not. We observed striking within-family associations for QAT, reflected by an Social Responsiveness Scale, second edition intraclass correlation of 0.77 in pairings of first degree relatives with NF1. Impairments in reciprocal social behavior and attention affect a large proportion of patients with NF1 throughout life and are often clinically unrecognized. Further exploration of genotype-phenotype correlation is strongly warranted for the purpose of gaining insights into mechanisms by which specific mutational variations in the NF1 gene may influence autistic trait severity. Copyright © 2015 Elsevier Inc. All rights reserved.
    The Journal of pediatrics 06/2015; 167(3). DOI:10.1016/j.jpeds.2015.04.075 · 3.79 Impact Factor
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    ABSTRACT: To evaluate evidence for differences in pediatric brain tumor diagnoses by race and ethnicity using a cross-sectional study design in individuals with neurofibromatosis type 1 (NF1). Subjects with NF1 were ascertained from the NF1 Patient Registry Initiative and through a clinical record database of patients at a large academic medical center. Logistic regression was employed to calculate ORs and 95% CIs to analyze differences in the odds of brain tumor diagnosis by race (White, Black, Asian, other/unknown) and ethnic (Hispanic vs non-Hispanic) groups. Data from a total of 1546, 629, and 2038 individuals who were ascertained from the NF1 Patient Registry Initiative, clinical records, and pooled datasets were analyzed, respectively. After adjusting for birth year, we observed a significantly reduced odds of brain tumor diagnoses in individuals self-identified or clinically reported as Black (OR = 0.13, 95% CI 0.05-0.31), Asian (OR = 0.15, 95% CI 0.04-0.64), and other/unknown (OR = 0.61, 95% CI 0.41-0.93) race compared with those with reported as White race. There was no significant difference in the odds of pediatric brain tumor diagnosis by Hispanic ethnicity. Consistent with prior smaller studies, these data suggest that pediatric brain tumor diagnoses vary by race in individuals with NF1. Reasons underlying observed differences by race warrant further investigation. Copyright © 2015 Elsevier Inc. All rights reserved.
    The Journal of pediatrics 05/2015; 167(3). DOI:10.1016/j.jpeds.2015.04.076 · 3.79 Impact Factor
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    ABSTRACT: Malignant peripheral nerve sheath tumors (MPNSTs) occur at increased frequency in individuals with neurofibromatosis type 1 (NF1), where they likely arise from benign plexiform neurofibroma precursors. While previous studies have employed a variety of discovery approaches to discover genes associated with MPNST pathogenesis, it is currently unclear what molecular events are associated with the evolution of MPNST from plexiform neurofibroma. Whole exome sequencing was performed on biopsy materials representing plexiform neurofibroma (n=3), MPNST, and metastasis from a single individual with NF1 over a 14-year period. Additional validation cases were used to assess candidate genes involved in malignant progression, while a murine MPNST model was employed for functional analysis. There was an increasing proportion of cells with a somatic NF1 gene mutation as the tumors progressed from benign to malignant, suggesting a clonal process in MPNST development. Copy number variations, including loss of one copy of the TP53 gene, were identified in the primary tumor and the metastatic lesion, but not in benign precursor lesions. A limited number of genes with non-synonymous somatic mutations (beta III-spectrin and ZNF208) were discovered, several of which were validated in additional primary and metastatic MPNST samples. Lastly, increased beta III-spectrin expression was observed in the majority of MPNSTs, and shRNA-mediated knockdown reduced murine MPNST growth in vivo. Collectively, the ability to track the molecular evolution of MPNST in a single individual with NF1 offers new insights into the sequence of genetic events important for disease pathogenesis and progression for future mechanistic study. Copyright © 2015, American Association for Cancer Research.
    Clinical Cancer Research 04/2015; 21(18). DOI:10.1158/1078-0432.CCR-14-3049 · 8.72 Impact Factor
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    ABSTRACT: Cognitive impairments are a major clinical feature of the common neurogenetic disease neurofibromatosis type 1 (NF1). Previous studies have demonstrated that increased neuronal inhibition underlies the learning deficits in NF1, however, the molecular mechanism underlying this cell-type specificity has remained unknown. Here, we identify an interneuron-specific attenuation of hyperpolarization-activated cyclic nucleotide-gated (HCN) current as the cause for increased inhibition in Nf1 mutants. Mechanistically, we demonstrate that HCN1 is a novel NF1-interacting protein for which loss of NF1 results in a concomitant increase of interneuron excitability. Furthermore, the HCN channel agonist lamotrigine rescued the electrophysiological and cognitive deficits in two independent Nf1 mouse models, thereby establishing the importance of HCN channel dysfunction in NF1. Together, our results provide detailed mechanistic insights into the pathophysiology of NF1-associated cognitive defects, and identify a novel target for clinical drug development.Molecular Psychiatry advance online publication, 28 April 2015; doi:10.1038/mp.2015.48.
    Molecular Psychiatry 04/2015; DOI:10.1038/mp.2015.48 · 14.50 Impact Factor
  • R Hugh · F Bender · Kevin M Haigis · David H Gutmann
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    ABSTRACT: Neural stem cells (NSCs) give rise to all the major cell types in the brain, including neurons, oligodendrocytes, and astrocytes. However, the intracellular signaling pathways that govern brain NSC proliferation and differentiation have been incompletely characterized to date. Since some neurodevelopmental brain disorders (Costello syndrome, Noonan syndrome) are caused by germline activating mutations in the RAS genes, Ras small GTPases are likely critical regulators of brain NSC function. In the mammalian brain, Ras exists as three distinct molecules (H-Ras, K-Ras, and N-Ras), each with different subcellular localizations, downstream signaling effectors, and biological effects. Leveraging a novel series of conditional activated Ras molecule-expressing genetically-engineered mouse strains, we demonstrate that activated K-Ras, but not H-Ras or N-Ras, expression increases brain NSC growth in a Raf-dependent, but Mek-independent, manner. Moreover, we show that activated K-Ras regulation of brain NSC proliferation requires Raf binding and suppression of retinoblastoma (Rb) function. Collectively, these observations establish tissue-specific differences in activated Ras molecule regulation of brain cell growth that operate through a non-canonical mechanism. This article is protected by copyright. All rights reserved. © 2015 AlphaMed Press.
    Stem Cells 03/2015; 33(6). DOI:10.1002/stem.1990 · 6.52 Impact Factor
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    ABSTRACT: Neurofibromatosis type 1 (NF1) is a common autosomal dominant neurologic condition characterized by significant clinical heterogeneity, ranging from malignant cancers to cognitive deficits. Recent studies have begun to reveal rare genotype-phenotype correlations, suggesting that the specific germline NF1 gene mutation may be one factor underlying disease heterogeneity. The purpose of this study was to define the impact of the germline NF1 gene mutation on brain neurofibromin function relevant to learning. Herein, we employ human NF1-patient primary skin fibroblasts, induced pluripotent stem cells (iPSCs) and derivative neural progenitor cells (NPCs) to demonstrate that NF1 germline mutations have dramatic effects on neurofibromin expression. Moreover, while all NF1-patient NPCs exhibit increased RAS activation and reduced cAMP generation, there was a neurofibromin dose-dependent reduction in dopamine levels. Additionally, we leveraged two complementary Nf1 genetically-engineered mouse (GEM) strains in which hippocampal-based learning and memory is dopamine-dependent to establish that neuronal dopamine levels and signaling as well as mouse spatial learning are controlled in an Nf1 gene dose-dependent manner. Collectively, this is the first demonstration that different germline NF1 gene mutations differentially dictate neurofibromin function in the brain. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Human Molecular Genetics 03/2015; 24(12). DOI:10.1093/hmg/ddv103 · 6.39 Impact Factor
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    ABSTRACT: The availability of adult malignant glioma stem cells (GSCs) has provided unprecedented opportunities to identify the mechanisms underlying treatment resistance. Unfortunately, there is a lack of comparable reagents for the study of pediatric low-grade glioma (LGG). Leveraging a neurofibromatosis 1 (Nf1) genetically engineered mouse LGG model, we report the isolation of CD133(+) multi-potent low-grade glioma stem cells (LG-GSCs), which generate glioma-like lesions histologically similar to the parent tumor following injection into immunocompetent hosts. In addition, we demonstrate that these LG-GSCs harbor selective resistance to currently employed conventional and biologically targeted anti-cancer agents, which reflect the acquisition of new targetable signaling pathway abnormalities. Using transcriptomic analysis to identify additional molecular properties, we discovered that mouse and human LG-GSCs harbor high levels of Abcg1 expression critical for protecting against ER-stress-induced mouse LG-GSC apoptosis. Collectively, these findings establish that LGG cancer stem cells have unique molecular and functional properties relevant to brain cancer treatment. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 03/2015; 10(11). DOI:10.1016/j.celrep.2015.02.041 · 8.36 Impact Factor
  • Nicole M Brossier · David H Gutmann
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    ABSTRACT: Children and adults with neurofibromatosis type 1 (NF1) are predisposed to developing CNS tumors, including optic pathway gliomas (OPGs), brainstem gliomas (BSGs) and high-grade gliomas. Although current first-line treatments for low-grade gliomas (OPGs and BSGs) may prevent further tumor growth, they rarely result in restoration of the associated visual or neurological deficits. The availability of accurate small-animal models of NF1-associated brain tumors has established tractable experimental platforms for the discovery and evaluation of promising therapeutic agents. On the basis of these preclinical studies, biologically targeted agents are now being evaluated in children with NF1-associated low-grade brain tumors. Collectively, these models have also begun to reveal potential neuroprotective and risk assessment strategies for this brain tumor-prone population.
    Expert Review of Anti-infective Therapy 02/2015; 15(4):1-9. DOI:10.1586/14737140.2015.1009043 · 3.46 Impact Factor
  • The Lancet Neurology 01/2015; 14(1):30-31. DOI:10.1016/S1474-4422(14)70298-4 · 21.90 Impact Factor
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    ABSTRACT: In the vertebrate central nervous system, myelinating oligodendrocytes are postmitotic and derive from proliferative oligodendrocyte precursor cells (OPCs). The molecular mechanisms that govern oligodendrocyte development are incompletely understood, but recent studies implicate the adhesion class of G protein-coupled receptors (aGPCRs) as important regulators of myelination. Here, we use zebrafish and mouse models to dissect the function of the aGPCR Gpr56 in oligodendrocyte development. We show that gpr56 is expressed during early stages of oligodendrocyte development. In addition, we observe a significant reduction of mature oligodendrocyte number and myelinated axons in gpr56 zebrafish mutants. This reduction results from decreased OPC proliferation, rather than increased cell death or altered neural precursor differentiation potential. Finally, we show that these functions are mediated by Gα12/13 proteins and Rho activation. Together, our data establish Gpr56 as a regulator of oligodendrocyte development.
    Nature Communications 01/2015; 6:6122. DOI:10.1038/ncomms7122 · 11.47 Impact Factor
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    ABSTRACT: Neurofibromatosis type 1 (NF1) was the first RASopathy and is now one of many RASopathies that are caused by germline mutations in genes that encode components of the Ras/mitogen-activated protein kinase (MAPK) pathway. Their common underlying pathogenetic etiology causes significant overlap in phenotypic features which includes craniofacial dysmorphology, cardiac, cutaneous, musculoskeletal, GI and ocular abnormalities, and a predisposition to cancer. The proceedings from the symposium "Recent Developments in Neurofibromatoses (NF) and RASopathies: Management, Diagnosis and Current and Future Therapeutic Avenues" chronicle this timely and topical clinical translational research symposium. The overarching goal was to bring together clinicians, basic scientists, physician-scientists, advocate leaders, trainees, students and individuals with Ras pathway syndromes to discuss the most state-of-the-art basic science and clinical issues in an effort to spark collaborations directed towards the best practices and therapies for individuals with RASopathies. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 01/2015; 167(1). DOI:10.1002/ajmg.a.36793 · 2.16 Impact Factor
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    ABSTRACT: Background Children with neurofibromatosis type 1 (NF1) develop optic pathway gliomas, which result from impaired NF1 protein regulation of Ras activity. One obstacle to the implementation of biologically targeted therapies is an incomplete understanding of the individual contributions of the downstream Ras effectors (mitogen-activated protein kinase kinase [MEK], Akt) to optic glioma maintenance. This study was designed to address the importance of MEK and Akt signaling to Nf1 optic glioma growth.
    Neuro-Oncology 12/2014; 17(6). DOI:10.1093/neuonc/nou329 · 5.56 Impact Factor
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    ABSTRACT: With increased internet accessibility worldwide, it is now possible to assemble individuals with rare diseases through web-based patient registries. However, the validity of participant-reported medical diagnoses is unknown. The objective of this study was to evaluate the accuracy of participant-reported Neurofibromatosis Type 1 (NF1) diagnoses among participants in the NF1 Patient Registry Initiative (NPRI). Subjects enrolled in the NPRI from 5/17/2011 to 7/7/2014 were included. Medical records (MRs) were obtained for participants who returned medical record release forms (MRRFs) during the study period. Participants were classified as having definite, probable, suspected, or no NF1 diagnosis based on MR information. To assess whether a returned MRRF served as a reliable marker of MR-documented NF1, we calculated the positive predictive value (PPV) as the proportion of individuals with MR-documented NF1 among those from whom MRs were obtained. We further examined whether a returned MRRF predicted the number of reported NF1 clinical signs in multivariable linear regression analyses. A total of 1456 individuals were included in the analyses. Of 416 individuals who returned MRRFs, 205 MRs were reviewed within the study period. The PPV ranged from 72.0 to 98.5% when including definite or definite/probable/suspected cases, respectively. The mean number of reported NF1 clinical signs was similar between those who returned (mean=3.3±1.2) and did not return (mean=3.2±1.3) their MRRFs. MRRF return was not a significant predictor of the number of NF1 clinical signs after adjusting for covariates. These data strongly suggest that individuals enrolling in the NPRI accurately report their NF1 diagnosis. Copyright © 2014 Elsevier Inc. All rights reserved.
    Contemporary Clinical Trials 12/2014; 40. DOI:10.1016/j.cct.2014.12.006 · 1.94 Impact Factor
  • David H Gutmann
    Neuro-Oncology 12/2014; 17(2). DOI:10.1093/neuonc/nou346 · 5.56 Impact Factor
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    Qian Liu · Nancy Zoellner · David H Gutmann · Kimberly J Johnson
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    ABSTRACT: One of the potential etiologies for non-familial Neurofibromatosis Type 1 (NF1) is increasing parental age. We sought to evaluate recent evidence for parental age effects in NF1 in a large study. Individuals with NF1 and a comparison group from the U.S. general population born between 1994 and 2012 were ascertained from the NF1 Patient Registry Initiative (NPRI) and the National Center for Vital Statistics, respectively. Multiple linear regression analysis was employed to identify differences between familial NF1, non-familial NF1, and U.S. population subjects in the mean parental ages at the time of the birth of offspring in each group. In addition, we also evaluated the effect of parental age on NF1 offspring with and without a pediatric brain tumor history. A total of 313 subjects from the NPRI (including 99 brain tumor cases) matched by birth year at a 1:3 ratio to U.S. general population births (n = 939) were included. Compared to the U.S. general population and familial NF1 cases, the mean paternal age for non-familial NF1 cases was 4.34 years (95 % CI 3.23-5.46, p ≤ 0.0001) and 3.39 years (95 % CI 1.57-5.20, p ≤ 0.0001) older, respectively, after adjusting for birth year. A similar pattern was observed for maternal age. There were no statistically significant differences in the mean maternal or paternal ages between NF1 offspring with and without a pediatric brain tumor. In conclusion, these data support a parental age effect for non-familial NF1 cases, but not for pediatric brain tumors in NF1.
    Familial Cancer 12/2014; 14(2). DOI:10.1007/s10689-014-9774-8 · 1.98 Impact Factor
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    American Journal of Medical Genetics Part A 12/2014; 164(12). DOI:10.1002/ajmg.a.36754 · 2.16 Impact Factor
  • David H Gutmann
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    ABSTRACT: Plexiform neurofibromas are one of the most common tumors encountered in individuals with the neurofibromatosis type I (NF1) cancer predisposition syndrome. In this issue of Cancer Cell, Chen and colleagues define the cell of origin for murine Nf1 plexiform neurofibroma and leverage this finding to develop a platform for preclinical drug evaluation. Plexiform neurofibromas are one of the most common tumors encountered in individuals with the neurofibromatosis type I (NF1) cancer predisposition syndrome. In this issue of Cancer Cell, Chen and colleagues define the cell of origin for murine Nf1 plexiform neurofibroma and leverage this finding to develop a platform for preclinical drug evaluation.
    Cancer cell 11/2014; 26(5):596-599. DOI:10.1016/j.ccell.2014.10.007 · 23.52 Impact Factor

Publication Stats

16k Citations
2,653.12 Total Impact Points


  • 1994–2015
    • Washington University in St. Louis
      • • Department of Neurology
      • • Department of Pediatrics
      San Luis, Missouri, United States
  • 2014
    • Ludwig Institute for Cancer Research
      La Jolla, California, United States
  • 2006–2014
    • Otto-von-Guericke-Universität Magdeburg
      • Institute for Neuropathology
      Magdeburg, Saxony-Anhalt, Germany
  • 2013
    • Guy's and St Thomas' NHS Foundation Trust
      • Department of Neurology
      Londinium, England, United Kingdom
  • 2008
    • Saint Louis University
      Сент-Луис, Michigan, United States
  • 2007
    • Mayo Foundation for Medical Education and Research
      Rochester, Michigan, United States
    • Emory University
      • Department of Pathology and Laboratory Medicine
      Atlanta, GA, United States
  • 1997–2007
    • University of Missouri - St. Louis
      Saint Louis, Michigan, United States
  • 2004
    • Medical University of South Carolina
      Charleston, South Carolina, United States
  • 2003
    • Mount Sinai Hospital
      New York City, New York, United States
    • SickKids
      • Arthur and Sonia Labatt Brain Tumour Research Centre (BTRC)
      Toronto, Ontario, Canada
  • 2002
    • King's College London
      • Department of Clinical Neuroscience
      Londinium, England, United Kingdom
    • Children's National Medical Center
      • Department of Neurology
      Washington, Washington, D.C., United States
    • Toronto Western Hospital
      Toronto, Ontario, Canada
  • 2001
    • Samuel Lunenfeld Research Institute
      Toronto, Ontario, Canada
    • University of Washington Seattle
      Seattle, Washington, United States
  • 1991–2001
    • University of Pennsylvania
      • Department of Neurology
      Filadelfia, Pennsylvania, United States
  • 1999
    • University of Iowa
      Iowa City, Iowa, United States
  • 1996
    • University of Toronto
      • Division of Neurosurgery
      Toronto, Ontario, Canada
  • 1991–1994
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 1992–1993
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
  • 1990–1992
    • Hospital of the University of Pennsylvania
      • Department of Neurology
      Philadelphia, Pennsylvania, United States