Support of the histaminergic hypothesis in Tourette Syndrome: association of the histamine decarboxylase gene in a large sample of families

Abstract

Background Gilles de la Tourette Syndrome is a neurodevelopmental disorder that is caused by the interaction of environment with a complex genetic background. The genetic etiology of the disorder remains, so far, elusive, although multiple promising leads have been recently reported. The recent implication of the histamine decarboxylase (HDC) gene, the key enzyme in histamine production, raises the intriguing hypothesis of a possible role of histaminergic dysfunction leading to TS onset. Methods Following up on the finding of a nonsense mutation in a single family with TS, we investigated variation across the HDC gene for association with TS. As a result of a collaborative international effort, we studied a large sample of 520 nuclear families originating from seven European populations (Greek, Hungarian, Italian, Polish, German, Albanian, Spanish) as well as a sample collected in Canada. Results and Conclusions Interrogating 12 tagging SNPs (tSNP) across the HDC region, we find strong over-transmission of alleles at two SNPs (rs854150 and rs1894236) in the complete sample, as well as a statistically significant associated haplotypes. Analysis of individual populations also reveals signals of association in the Canadian, German and Italian samples. Our results provide strong support for the histaminergic hypothesis in TS etiology and point to a possible role of histamine pathways in neuronal development.

Histaminergic modulation in Tourette syndrome

“…A more general association of histaminergic pathways with TS was identified by analysis of rare CNVs in a subsequent study [77]. The hypothesis of an involvement of the histaminergic system in the pathogenesis of TS was also supported by a more recent report on single nucleotide polymorphisms in the HDC region that are associated with TS [78]. However, HDC mutations were not replicated in larger scale studies [76], suggesting that these genetic alterations may only be responsible for a subset of patients with TS.…”

“…The identification of the previously mentioned HDC mutation led to a study in 2013 that investigated variations across the whole HDC gene [78]. This study involved 520 families with TS from seven European Countries.…”

The Histamine H3 Receptor Differentially Modulates Mitogen-activated Protein Kinase (MAPK) and Akt Signaling in Striatonigral and Striatopallidal Neurons

“…A dominant-acting loss-of-function mutation in the HA biosynthetic enzyme histidine decarboxylase (Hdc) has been implicated as a rare cause of Tourette syndrome (16); other genetic analyses have suggested abnormalities in histaminergic signaling in Tourette syndrome more broadly (17,18). HDC protein is particularly concentrated in the striatum, suggesting an important role for HA there (19).…”

Tourette Syndrome research highlights 2014

“…Castellan Baldan et al 1, 2 report on characterization of a possible animal model for Tourette syndrome, chosen because of a family with Tourette syndrome linked to a loss-of-function mutation in the histidine decarboxylase gene 3, 4 . Histidine decarboxylase knock-out mice 5 exhibited tic-like stereotypies after a D-amphetamine challenge (see Figure 1, panel E in ref.…”