Tourette syndrome is not caused by mutations in the central cannabinoid receptor (CNR1) gene

Tourette syndrome (TS) is a complex inherited disorder of unknown aetiology, characterized by multiple motor and vocal tics. Involvement of the central cannabinoid (CB1) system is suggested because of therapeutic effects of marijuana (Cannabis sativa L.) consumption and Delta(9)-tetrahydrocannabinol (-THC) treatment in TS patients. The central cannabinoid receptor (CNR1) gene encoding the CNR1 was considered as a candidate gene for TS and systematically screened by single-strand conformation polymorphism (SSCP) analysis and sequencing. Compared with the published CNR1 sequence, three single base substitutions were identified: 1326T --> A, 1359G --> A, 1419 + 1G --> C. The change at position 1359 is a common polymorphism (1359 G/A) without allelic association with TS. 1326T --> A was present in only one TS patient and is a silent mutation which does not change codon 442 (valine). 1419 + 1G --> C affects the first nucleotide immediately following the coding sequence. It was first detected in three of 40 TS patients and none of 81 healthy controls. This statistically significant association with TS (P = 0.034) could not be confirmed in two subsequent cohorts of 56 TS patients (one heterozygous for 1419 + 1G --> C) and 55 controls and 64 patients and 66 controls (one heterozygous for 1419 + 1G --> C), respectively. Transcript analysis of lymphocyte RNA from 5 1419 + 1G --> C carriers revealed no systematic influence on the expression level of the mutated allele. In addition, segregation analysis of 1419 + 1G --> C in affected families gave evidence that 1419 + 1G --> C does not play a causal role in the aetiology of TS. We conclude that genetic variations of the CNR1 gene are not a plausible explanation for the clinically observed relation between the cannabinoid system and TS.