title: A single gene defect causing claustrophobia.
abstract: Claustrophobia, the well-known fear of being trapped in narrow/closed spaces, is often considered a conditioned response to traumatic experience. Surprisingly, we found that mutations affecting a single gene, encoding a stress-regulated neuronal protein, can cause claustrophobia. Gpm6a-deficient mice develop normally and lack obvious behavioral abnormalities. However, when mildly stressed by single-housing, these mice develop a striking claustrophobia-like phenotype, which is not inducible in wild-type controls, even by severe stress. The human GPM6A gene is located on chromosome 4q32-q34, a region linked to panic disorder. Sequence analysis of 115 claustrophobic and non-claustrophobic subjects identified nine variants in the noncoding region of the gene that are more frequent in affected individuals (P=0.028). One variant in the 3'untranslated region was linked to claustrophobia in two small pedigrees. This mutant mRNA is functional but cannot be silenced by neuronal miR124 derived itself from a stress-regulated transcript. We suggest that loosing dynamic regulation of neuronal GPM6A expression poses a genetic risk for claustrophobia.
authors: Division of Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors: A
authors: A
authors: El-Kordi
authors: A
authors: A
authors: Kästner
authors: S
authors: S
authors: Grube
authors: M
authors: M
authors: Klugmann
authors: M
authors: M
authors: Begemann
authors: S
authors: S
authors: Sperling
authors: K
authors: K
authors: Hammerschmidt
authors: C
authors: C
authors: Hammer
authors: B
authors: B
authors: Stepniak
authors: J
authors: J
authors: Patzig
authors: P
authors: P
authors: de Monasterio-Schrader
authors: N
authors: N
authors: Strenzke
authors: G
authors: G
authors: Flügge
authors: H B
authors: HB
authors: Werner
authors: R
authors: R
authors: Pawlak
authors: K-A
authors: KA
authors: Nave
authors: H
authors: H
authors: Ehrenreich
mesh_terms: D000328:Adult; D000679:Amygdala / Q000737:chemistry; D000818:Animals; D001522:Behavior, Animal; D004596:Electroretinography; D005260:Female; D005818:Genetic Engineering / Q000379:methods; D006579:Heterozygote; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010698:Phobic Disorders / Q000235:genetics*; D011581:Psychological Tests; D013216:Reflex, Startle / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013315:Stress, Psychological / Q000235:genetics
chemical_list: C484158:GPM6A protein, human; C083480:Gpm6a protein, mouse; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins
references: Steroids. 2009 Nov;74(12):938-44
references: 19577584
references: J Neurosci. 2006 Nov 8;26(45):11743-52
references: 17093095
references: Cell Res. 2008 Jul;18(7):768-79
references: 18574501
references: Behav Brain Res. 2009 Dec 1;204(1):246-9
references: 19482043
references: J Neurosci. 1996 Dec 15;16(24):7920-9
references: 8987820
references: Genes Dev. 2007 Mar 1;21(5):531-6
references: 17344415
references: Invest Ophthalmol Vis Sci. 2001 Feb;42(2):506-13
references: 11157890
references: Mol Cell Neurosci. 2001 Dec;18(6):593-605
references: 11749036
references: BMC Psychiatry. 2010 Nov 10;10:91
references: 21067598
references: Genome Med. 2010 Jun 29;2(6):40
references: 20587004
references: Neuron. 1993 Sep;11(3):423-31
references: 8398137
references: J Med Genet. 2011 Jun;48(6):361-8
references: 21493958
references: J Mol Neurosci. 2013 May;50(1):33-57
references: 22836882
references: Nat Genet. 2004 Dec;36(12):1319-25
references: 15565110
references: Am J Psychiatry. 2010 Mar;167(3):312-20
references: 20048022
references: AJR Am J Roentgenol. 1989 Mar;152(3):653
references: 2783823
references: Am J Med Genet B Neuropsychiatr Genet. 2008 Sep 5;147B(6):707-11
references: 18163405
references: Physiol Behav. 2012 Dec 5;107(5):699-710
references: 22429904
references: FASEB J. 2008 Dec;22(12):4085-95
references: 18716031
references: J Neurochem. 2011 Nov;119(3):521-31
references: 21426347
references: J Behav Med. 1998 Jun;21(3):255-68
references: 9642571
references: PLoS One. 2011 Feb 09;6(2):e16883
references: 21347384
references: J Behav Med. 1990 Aug;13(4):391-401
references: 2246785
references: Biochem Biophys Res Commun. 2002 Oct 4;297(4):722-8
references: 12359212
references: J Neurosci. 2006 Mar 1;26(9):2458-66
references: 16510724
references: Neuron. 2009 Sep 24;63(6):803-17
references: 19778509
references: Eur J Neurosci. 2004 Feb;19(3):659-66
references: 14984416
references: Stem Cells Dev. 2009 May;18(4):629-39
references: 19298174
references: Nat Rev Neurosci. 2005 Jun;6(6):463-75
references: 15891777
references: Nat Neurosci. 2009 Apr;12(4):399-408
references: 19287386
references: Behav Brain Res. 2013 Aug 15;251:41-9
references: 23183221
references: Neuron Glia Biol. 2008 May;4(2):111-27
references: 19497142
references: Proc Natl Acad Sci U S A. 2005 Nov 22;102(47):17196-201
references: 16286650
references: J Anxiety Disord. 2001 Jul-Aug;15(4):287-97
references: 11474815
references: Mol Cell Neurosci. 2009 Dec;42(4):350-62
references: 19703567
references: J Neurobiol. 1992 Feb;23(1):71-88
references: 1564456
references: Psychopharmacology (Berl). 1983;81(4):286-91
references: 6419256
references: J Mol Neurosci. 2009 Mar;37(3):191-200
references: 18581270
references: J Neurosci Res. 1997 Dec 1;50(5):829-43
references: 9418970
references: Glia. 2013 Apr;61(4):567-86
references: 23322581
references: Nature. 2011 May 19;473(7347):372-5
references: 21508957
references: J Neurosci Res. 2004 Dec 1;78(5):702-10
references: 15505804