title: Heterozygous PAX6 mutation, adult brain structure and fronto-striato-thalamic function in a human family.
abstract: Recent progress in developmental neurobiology and neuroimaging can be drawn together to provide new insight into the links between genetically specified processes of embryonic brain development and adult human brain structure and function. We used magnetic resonance imaging (MRI) to show that individuals with aniridia and deficits in executive and social cognition, due to heterozygous mutation of the neurodevelopmental control gene PAX6, have structural abnormalities of grey matter in anterior cingulate cortex, cerebellum and medial temporal lobe, as well as white matter deficits in corpus callosum. Functional MRI demonstrated reduced activation of fronto-striato-thalamic systems during performance of overt verbal fluency and nonsense sentence completion; the most consistent abnormality of verbal executive activation was located in the thalamus. These results provide the first evidence for brain functional differences in humans with PAX6 mutation that are compatible both with anatomical abnormalities in the same subjects and, more circumstantially, with the known roles of murine Pax6 in regional differentiation, axonal guidance and other aspects of early forebrain development. Highly conserved homeobox genes may be critical for normal ontogenesis of large-scale neurocognitive networks supporting phylogenetically advanced mental functions.
authors.affiliation: Institute of Psychiatry, King's College London, De Crespigny Park, London SE5 8AF, UK.
authors.forename: Zoë
authors.initials: Z
authors.lastname: Ellison-Wright
authors.forename: Isobel
authors.initials: I
authors.lastname: Heyman
authors.forename: Ian
authors.initials: I
authors.lastname: Frampton
authors.forename: Katya
authors.initials: K
authors.lastname: Rubia
authors.forename: Xavier
authors.initials: X
authors.lastname: Chitnis
authors.forename: Ian
authors.initials: I
authors.lastname: Ellison-Wright
authors.forename: Steve C R
authors.initials: SC
authors.lastname: Williams
authors.forename: John
authors.initials: J
authors.lastname: Suckling
authors.forename: Andrew
authors.initials: A
authors.lastname: Simmons
authors.forename: Edward
authors.initials: E
authors.lastname: Bullmore
mesh_terms: D000293:Adolescent; D000328:Adult; D015783:Aniridia / Q000150:complications / Q000235:genetics; D001921:Brain / Q000033:anatomy & histology / Q000502:physiology*; D001931:Brain Mapping; D016022:Case-Control Studies; D003072:Cognition Disorders / Q000209:etiology / Q000235:genetics; D005136:Eye Proteins; D005192:Family Health; D005260:Female; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D009154:Mutation; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D012097:Repressor Proteins; D012924:Social Conditions; D014705:Verbal Behavior / Q000502:physiology
chemical_list: D005136:Eye Proteins; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; D012097:Repressor Proteins