Elucidating the impact of neurofibromatosis-1 germline mutations on neurofibromin function and dopamine-based learning

Human Molecular Genetics
Corina AnastasakiD H Gutmann

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 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 cyclic AMP generation, there was a neurofibromin dose-dependent reduction in dopamine (DA) levels. Additionally, we leveraged two complementary Nf1 genetically-engineered mouse strains in which hippocampal-based learning and memory is DA-dependent to establish that neuronal DA levels and signaling as well as mouse spatial learning are controlled in an Nf1 gene dose-dependent manner. Collectively, this is the first dem...Continue Reading

References

Aug 1, 1995·Human Molecular Genetics·S HoffmeyerW Krone
May 15, 2002·Developmental Medicine and Child Neurology·Victor-F MautnerRobert A Leark
Jun 22, 2002·Molecular and Cellular Biology·Michaela Livia BajenaruDavid H Gutmann
Mar 28, 2003·American Journal of Human Genetics·T De RaedtE Legius
Sep 29, 2004·Genesis : the Journal of Genetics and Development·Jonas LindebergTed Ebendal
Jul 18, 2008·JAMA : the Journal of the American Medical Association·Lianne C KrabYpe Elgersma
Dec 23, 2009·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Kimberly Jett, Jan M Friedman
Apr 23, 2010·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Jacquelyn A BrownDavid H Gutmann
Jul 16, 2010·Journal of Psychiatric Research·Davide CarlinoMaurizio De Vanna
Sep 10, 2010·Human Molecular Genetics·Jacquelyn A BrownDavid H Gutmann
Sep 30, 2010·Molecular Psychiatry·E SchwarzS Bahn
Apr 5, 2011·The American Journal of Pathology·Eeva-Mari JouhilahtiJuha Peltonen
Aug 25, 2011·Nature Communications·Michael J DevineTilo Kunath
Sep 9, 2011·Human Molecular Genetics·Takuya YagiNorihiro Suzuki
Apr 13, 2012·Journal of Child Neurology·Jill C IsenbergDavid H Gutmann
May 15, 2012·Neurogenetics·Hildegard Kehrer-SawatzkiVictor-Felix Mautner
Dec 12, 2012·Annals of Neurology·Kelly A Diggs-AndrewsDavid H Gutmann
Jul 30, 2014·Human Molecular Genetics·Corina Anastasaki, David H Gutmann

❮ Previous
Next ❯

Citations

Feb 26, 2016·Human Molecular Genetics·Joseph A ToonenDavid H Gutmann
Dec 8, 2015·Glia·Suzanne J BakerDavid H Gutmann
May 14, 2016·Expert Review of Neurotherapeutics·David H Gutmann
Jun 9, 2016·Seminars in Cell & Developmental Biology·Laura J SmithsonDavid H Gutmann
Jul 28, 2016·Frontiers in Human Neuroscience·Danielle de Souza CostaDébora M de Miranda
Sep 13, 2016·Laboratory Investigation; a Journal of Technical Methods and Pathology·Hua LiMargaret R Wallace
Jan 31, 2017·Annual Review of Pathology·Courtney L MonroeDavid H Gutmann
Dec 17, 2017·Journal of Child Neurology·Cynthia J Campen, David H Gutmann
Apr 29, 2018·Journal of Neuroscience Research·Morgan E Freret, David H Gutmann
Dec 15, 2019·The Journal of Biological Chemistry·Mukul SherekarDominic Esposito
Sep 29, 2017·Neurology. Genetics·Corina AnastasakiDavid H Gutmann
Jan 10, 2017·Frontiers in Oncology·Cora A RickerCharles Keller
Sep 2, 2017·Annual Review of Genomics and Human Genetics·Sarah C BorrieClaudia Bagni
Jul 27, 2018·Journal of Molecular Neuroscience : MN·Heng XiaoHao Deng
Dec 17, 2019·Journal of Attention Disorders·Jonathan M PayneKathryn N North
Jul 10, 2020·Neuro-oncology Advances·Amanda De Andrade Costa, David H Gutmann
Dec 12, 2017·Human Molecular Genetics·Matthew A SummersAaron Schindeler
Oct 20, 2017·Pediatric Blood & Cancer·Soumen KhatuaRoger J Packer
Feb 6, 2020·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Myrthe J OttenhoffYpe Elgersma
Aug 27, 2017·Autism Research : Official Journal of the International Society for Autism Research·Susan E MaloneyJoseph D Dougherty
Aug 15, 2017·Neurology. Genetics·Corina AnastasakiDavid H Gutmann
Oct 31, 2020·Cells·Mohammed BergougHélène Bénédetti
Apr 11, 2017·Experimental Neurology·Michelle L WegscheidDavid H Gutmann
Aug 11, 2020·Journal of the American Academy of Dermatology·Britney N WilsonRobert A Schwartz

❮ Previous
Next ❯

Related Concepts

Related Feeds

Basal Forebrain- Circuits

Basal forebrain is a region in the brain important for production of acetylcholine and is the major cholinergic output of the CNS. Discover the latest research on circuits in the basal forebrain here.