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A single gene defect causing claustrophobia

2013; Springer Nature; Volume: 3; Issue: 4 Linguagem: Inglês

10.1038/tp.2013.28

2158-3188

Ahmed El-Kordi, Anne Kästner, Sabrina Grube, Matthias Klugmann, Martin Begemann, Swetlana Sperling, Kurt Hammerschmidt, Christian Hammer, Beata Stepniak, Julia Patzig, Patricia de Monasterio‐Schrader, Nicola Strenzke, G. Flügge, Hauke Werner, Robert Pawlak, KA Nave, Hannelore Ehrenreich,

Neuroendocrine regulation and behavior

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.