Sequence Variants in SLITRK1 Are Associated with Tourette's Syndrome

Abstract

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.

Arginase II Contributes to the Ca 2+ /CaMKII/eNOS Axis by Regulating Ca 2+ Concentration Between the Cytosol and Mitochondria in a p32‐Dependent Manner

“…NO generated by eNOS increases mitochondrial biogenesis and enhances respiration and ATP content 40. Reciprocally, arginase inhibition increased NO production, and L‐Arg supplementation increased [Ca 2+ ]c (Figure 4A).…”

Functional SLITRK1 var321, varCDfs and SLC6A4 G56A variants and susceptibility to obsessive-compulsive disorder

“…Abelson et al 1 did not observe SLITRK1 var321 in 4296 control chromosomes in primarily Caucasian and African-American ethnicities. With the var321 variant discovered here being only the fourth confirmed allele besides the two TS probands and one family member, further analyses in even larger populations are warranted.…”

“…1,2 Here, we investigated these gene variants in obsessivecompulsive disorder (OCD), based on high degrees of TS/OCD comorbidity, plus G56A functionally resembling SLC6A4 I425 V in producing transporter gain-offunction. [2][3][4] SLITRK1 was uncovered as a candidate for TS owing to its < 230 kb proximity to a breakpoint of a 13q chromosomal inversion found in a child with TS and attention-deficit/hyperactivity disorder (ADHD), in addition to its role in neurite outgrowth.…”

“…[2][3][4] SLITRK1 was uncovered as a candidate for TS owing to its < 230 kb proximity to a breakpoint of a 13q chromosomal inversion found in a child with TS and attention-deficit/hyperactivity disorder (ADHD), in addition to its role in neurite outgrowth. 1 Furthermore, screening of 174 additional TS probands for SLITRK1 variants revealed a truncating frameshift mutation, varCDfs, with complete loss of function in one, and a microRNA domain-affecting variant, var321, which leads to reduced reporter gene activity in vitro, in two other of these probands (Table 1). 1 Because B40% of TS probands have OCD or at least moderate obsessive-compulsive symptoms, 5 and because of the specific overlap of tics, TS and OC symptoms in the four families with 13q and SLITRK1 anomalies and variants, 1 we performed a case-control association study and genotyped 322 OCD probands and 390 controls for SLITRK1 var321 and varCDfs.…”

“…1 Furthermore, screening of 174 additional TS probands for SLITRK1 variants revealed a truncating frameshift mutation, varCDfs, with complete loss of function in one, and a microRNA domain-affecting variant, var321, which leads to reduced reporter gene activity in vitro, in two other of these probands (Table 1). 1 Because B40% of TS probands have OCD or at least moderate obsessive-compulsive symptoms, 5 and because of the specific overlap of tics, TS and OC symptoms in the four families with 13q and SLITRK1 anomalies and variants, 1 we performed a case-control association study and genotyped 322 OCD probands and 390 controls for SLITRK1 var321 and varCDfs. The probands met DSM-IV criteria for OCD and were comprised of 156 female and 123 male subjects of Caucasian ethnicity as well as 25 female and 18 male subjects of other ethnicities (details in the legend of Table 2).…”