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Susceptibility to Tourette's syndrome is known to have a genetic influence. This study, of a nonconsanguineous family in which the father and his eight children are affected by the disorder, implicates a deficit in L-histidine decarboxylase activity as one potential cause of the disorder. This study of a nonconsanguineous family in which the father and his eight children are affected by Tourette's syndrome implicates a deficit in L-histidine decarboxylase activity as one potential cause of the disorder. Tourette's syndrome is characterized by childhood onset, waxing and waning symptomatology, and typically, improvement in adulthood. The molecular underpinnings of the disorder remain uncertain, although multiple lines of evidence suggest involvement of dopaminergic neurotransmission and abnormalities involving cortical–striatal–thalamic–cortical circuitry. 1 Current treatment focuses on tic reduction and management of prevalent coexisting conditions such as obsessive–compulsive disorder and attention deficit–hyperactivity disorder. However, therapeutic options have limited efficacy and may carry clinically significant side effects. Consequently, the development of new treatments based on an improved understanding of disease pathophysiology is a high priority. 2 The large genetic contribution to Tourette's syndrome is well established. . . .

Tourette's syndrome (TS) is a genetically influenced developmental neuropsychiatric disorder characterized by chronic vocal and motor tics. We studied Slit and Trk-like 1 (SLITRK1) as a candidate gene on chromosome 13q31.1 because of its proximity to a de novo chromosomal inversion in a child with TS. Among 174 unrelated probands, we identified a frameshift mutation and two independent occurrences of the identical variant in the binding site for microRNA hsa-miR-189. These variants were absent from 3600 control chromosomes. SLITRK1 mRNA and hsa-miR-189 showed an overlapping expression pattern in brain regions previously implicated in TS. Wild-type SLITRK1, but not the frameshift mutant, enhanced dendritic growth in primary neuronal cultures. Collectively, these findings support the association of rare SLITRK1 sequence variants with TS.

Tourette's syndrome is a common developmental neuropsychiatric disorder characterized by chronic motor and vocal tics. Despite a strong genetic contribution, inheritance is complex, and risk alleles have proven difficult to identify. Here, we describe an analysis of linkage in a two-generation pedigree leading to the identification of a rare functional mutation in the HDC gene encoding L-histidine decarboxylase, the rate-limiting enzyme in histamine biosynthesis. Our findings, together with previously published data from model systems, point to a role for histaminergic neurotransmission in the mechanism and modulation of Tourette's syndrome and tics.

Tourette syndrome (TS) is an inherited neuropsychiatric disorder that is characterized by chronic motor and vocal tics. The clinical heterogeneity of the disorder is truly a complicating factor in elucidating the genetic basis for the disorder. It may be that there is no definitive causative gene for TS, but multiple contributing alleles. By identifying rare TS cases and associated rare variants, we can gain insight into the gene pathway(s) involved in the pathophysiology of TS. We used this rare variant approach to identify a promising gene, Slit and Trk-like family member 1 (SLITRK1), in a TS patient with a chromosomal abnormality. The function of SLITRK1 is not known and therefore we sought to further characterize SLITRK1 through expression analyses and identification of binding partners. We found that SLITRK1 is developmentally regulated in the cortico-striatal circuitry, which is implicated in TS. Despite multiple screens for interactors for the extracellular domain of SLITRK1, none were identified. However, expression profiling of SLITRK1 cell lines has lead to several potential and interesting pathways. Recently, through genetic analysis of a rare TS pedigree, we also identified a causative mutation in the gene Histidine Decarboxylase (HDC). Functional analysis determined that this mutation resulted in a dominant negative phenotype. The histaminergic pathway is a strong candidate for a causal mechanism in TS. Through identification and characterization of these rare variants associated with TS, we hope to further our understanding of the mechanisms contributing to the pathophysiology of TS.