RESUMO
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.
Assuntos
Glicoproteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Transtornos Fóbicos/genética , Adulto , Tonsila do Cerebelo/química , Animais , Comportamento Animal , Eletrorretinografia , Feminino , Engenharia Genética/métodos , Heterozigoto , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Testes Psicológicos , Reflexo de Sobressalto/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estresse Psicológico/genéticaRESUMO
The expression of the human cyp19 gene, encoding P450 aromatase, the key enzyme for estrogen biosynthesis, involves alternative splicing of multiple forms of exon I regulated by different promoters. Aromatase expression has been detected in the human cerebral cortex, although the precise cellular distribution and promoter regulation are not fully characterized. We examined the variants of exon I of cyp19 by PCR analysis and the cellular distribution of the enzyme using immunohistochemistry in the human temporal cortex. We detected four different variants of exon I, suggesting a complex regulation of cyp19 in the cerebral cortex. In addition, the enzyme was localized mainly in a large subpopulation of pyramidal neurons and in a subpopulation of astrocytes. However, the majority of GABAergic interneurons identified by their expression of the calcium-binding proteins calbindin, calretinin and parvalbumin, did not display aromatase immunoreactivity. The broad range of potential modulators of the cyp19 gene in the cortex and the widespread expression of the protein in specific neuronal and glial subpopulations suggest that local estrogen formation may play an important role in human cortical function.
