Brain Advance Access originally published online on September 4, 2003
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Brain, Vol. 126, No. 11, 2431-2446,
November 2003
© 2003 Guarantors of Brain
doi: 10.1093/brain/awg242
Dosage-sensitive X-linked locus influences the development of amygdala and orbitofrontal cortex, and fear recognition in humans
1 Wellcome Department of Imaging Neuroscience, Institute of Neurology, 2 Behavioural and Brain Sciences Unit, Institute of Child Health, London, 3 Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, UK, 4 Department of Neuroscience, Section of Pharmacology, BMC, Uppsala, Sweden and 5 Instituto Santa Lucia, Rome, Italy
Correspondence to: David Skuse, Behavioural and Brain Sciences Unit, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK. E-mail: dskuse{at}ich.ucl.ac.uk
The amygdala, which plays a critical role in emotional learning and social cognition, is structurally and functionally sexually dimorphic in humans. We used magnetic neuroimaging and molecular genetic analyses with healthy subjects and patients possessing X-chromosome anomalies to find dosage-sensitive genes that might influence amygdala development. If such X-linked genes lacked a homologue on the Y-chromosome they would be expressed in one copy in normal 46,XY males and two copies in normal 46,XX females. We showed by means of magnetic neuroimaging that 46,XY males possess significantly increased amygdala volumes relative to normal 46,XX females. However, females with Turner syndrome (45,X) have even larger amygdalae than 46,XY males. This finding implies that haploinsufficiency for one or more X-linked genes influences amygdala development irrespective of a direct or indirect (endocrinological) mechanism involving the Y-chromosome. 45,X females also have increased grey matter volume in the orbitofrontal cortex bilaterally, close to a region implicated in emotional learning. They are as poor as patients with bilateral amygdalectomies in the recognition of fear from facial expressions. We attempted to localize the gene(s) responsible for these deficits in X-monosomy by means of a deletion mapping strategy. We studied female patients possessing structural X-anomalies of the short arm. A genetic locus (no greater than 4.96 Mb in size) at Xp11.3 appears to play a key role in amygdala and orbitofrontal structural and (by implication) functional development. Females with partial X-chromosome deletions, in whom this critical locus is deleted, have normal intelligence. Their fear recognition is as poor as that of 45,X females and their amygdalae are correspondingly enlarged. This 4.96 Mb region contains, among others, the genes for monoamine oxidase A (MAOA) and B (MAOB), which are involved in the oxidative deamination of several neurotransmitters, including dopamine and serotonin. Abnormal activity of these neurotransmitters has been implicated in the aetiology of several neurodevelopmental disorders in which social cognitive deficits are prominent. These associated deficits include a specific lack of fear recognition from facial expressions. We show that the thrombocytic activity of MAOB is proportionate to the number of X-chromosomes, and hypothesize that haploinsufficiency of this enzyme in 45,X females predisposes to their deficits in social cognition.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  H. Yamasue, O. Abe, M. Suga, H. Yamada, M. A. Rogers, S. Aoki, N. Kato, and K. Kasai Sex-Linked Neuroanatomical Basis of Human Altruistic Cooperativeness Cereb Cortex, October 1, 2008; 18(10): 2331 - 2340. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Xu, X. Deng, R. Watkins, and C. M. Disteche Sex-Specific Differences in Expression of Histone Demethylases Utx and Uty in Mouse Brain and Neurons J. Neurosci., April 23, 2008; 28(17): 4521 - 4527. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. A. Weiss, S. Purcell, S. Waggoner, K. Lawrence, D. Spektor, M. J. Daly, P. Sklar, and D. Skuse Identification of EFHC2 as a quantitative trait locus for fear recognition in Turner syndrome Hum. Mol. Genet., January 1, 2007; 16(1): 107 - 113. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Skuse Genetic influences on the neural basis of social cognition Phil Trans R Soc B, December 29, 2006; 361(1476): 2129 - 2141. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. J. Marco and D. H. Skuse Autism-lessons from the X chromosome Soc Cogn Affect Neurosci, December 1, 2006; 1(3): 183 - 193. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. H Skuse Sexual dimorphism in cognition and behaviour: the role of X-linked genes Eur. J. Endocrinol., November 1, 2006; 155(suppl_1): S99 - S106. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. K. Pinsonneault, A. C. Papp, and W. Sadee Allelic mRNA expression of X-linked monoamine oxidase a (MAOA) in human brain: dissection of epigenetic and genetic factors Hum. Mol. Genet., September 1, 2006; 15(17): 2636 - 2649. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Meyer-Lindenberg, J. W. Buckholtz, B. Kolachana, A. R. Hariri, L. Pezawas, G. Blasi, A. Wabnitz, R. Honea, B. Verchinski, J. H. Callicott, et al. Neural Mechanisms of Genetic Risk for Impulsivity and Violence in Humans Focus, August 1, 2006; 4(3): 360. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Holzapfel, N. Barnea-Goraly, M. A. Eckert, S. R. Kesler, and A. L. Reiss Selective alterations of white matter associated with visuospatial and sensorimotor dysfunction in turner syndrome. J. Neurosci., June 28, 2006; 26(26): 7007 - 7013. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Meyer-Lindenberg, J. W. Buckholtz, B. Kolachana, A. R. Hariri, L. Pezawas, G. Blasi, A. Wabnitz, R. Honea, B. Verchinski, J. H. Callicott, et al. From the Cover: Neural mechanisms of genetic risk for impulsivity and violence in humans PNAS, April 18, 2006; 103(16): 6269 - 6274. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. J Giltay, K. H Kho, B. A Blansjaar, M. M Verbeek, P B. H Geurtz, J. M Geleijnse, and L. J G Gooren The sex difference of plasma homovanillic acid is unaffected by cross-sex hormone administration in transsexual subjects J. Endocrinol., October 1, 2005; 187(1): 109 - 116. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. H. Skuse, J. S. Morris, and R. J. Dolan Functional dissociation of amygdala-modulated arousal and cognitive appraisal, in Turner syndrome Brain, September 1, 2005; 128(9): 2084 - 2096. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. H. Skuse X-linked genes and mental functioning Hum. Mol. Genet., April 15, 2005; 14(suppl_1): R27 - R32. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. R. Isles, W. Davies, D. Burrmann, P. S. Burgoyne, and L. S. Wilkinson Effects on fear reactivity in XO mice are due to haploinsufficiency of a non-PAR X gene: implications for emotional function in Turner's syndrome Hum. Mol. Genet., September 1, 2004; 13(17): 1849 - 1855. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. L. Reiss, M. A. Eckert, F. E. Rose, A. Karchemskiy, S. Kesler, M. Chang, M. F. Reynolds, H. Kwon, and A. Galaburda An Experiment of Nature: Brain Anatomy Parallels Cognition and Behavior in Williams Syndrome J. Neurosci., May 26, 2004; 24(21): 5009 - 5015. [Abstract] [Full Text] [PDF]
|
|