Trends in Genetics
Research FocusA new gene for Tourette's syndrome: a window into causal mechanisms?
Introduction
In the 19th century, Jean-Marc Gaspard Itard, Gilles de la Tourette and others identified the occurrence of tics – stereotyped, suppressible but, generally, involuntary motor movements – in individuals who also had concomitant ritualistic and disruptive behaviors. On assignment from Jean M. Charcot, Gilles de la Tourette diligently reported nine patients with tics, identifying a hereditary profile, a male gender bias, a childhood onset and few signs of intellectual deterioration [1]. The new disorder was named Gilles de la Tourette syndrome (GTS), and a key clinical feature was its association with obsessions (intrusive ideations, impulses or urges) and compulsions (repetitive behaviors). Renewed interest in GTS in the late 20th century [2] led to the study of the underlying genetic component of the disorder [3], which initially included a dominant gene hypothesis [4], and the observation that obsessive-compulsive disorder (OCD) could be an alternative phenotype [4]. Currently, genetic research in GTS comprises multiple linkage and association studies with mixed results [5]. No susceptibility gene has been identified and a complex etiology reflecting an interplay between vulnerability genes and environmental factors is suspected [6]. However, recently an article by Abelson et al. reported a novel gene (SLITRK1, Genbank accession no. NM_052910) and a putative mechanism for its influence on the phenotypic expression of GTS [7].
The premise that sporadic chromosomal rearrangements can lead to identification of chromosomal regions, and eventually genes, is a plausible working hypothesis when pursuing elusive genes in complex disorders such as GTS. New technologies such as comparative genomic hybridization (CGH) can scan the whole genome and detect DNA gains or losses, although not balanced translocations, and accelerate the process [8]. Following the logic of searching for patients with DNA alterations associated with the phenotype, Abelson et al. identified an individual with GTS, who (i) had no family history of GTS, attention-deficit hyperactivity disorder (ADHD) or obsessive-compulsive disorder (OCD) and; (ii) had an inversion inv(13) (q31.1; q33.1). Fine mapping with fluorescent in situ hybridization (FISH) and bacterial artificial chromosomes (BACs) were used to localize chromosomal breakpoints. Among the potential culprit genes that could be related to the breakpoints, SLITRK1 (OMIM #609678) was notable for its central nervous system (CNS) expression, and previous work on SLITRK1 indicated its potential role in the pathophysiology of neurodevelopmental disorders.
Section snippets
Are GTS, OCD and trichotillomania related disorders?
SLITRK1 is a member of the family of SLITRK genes, which participate in the growth of axons and dendrites (neurites) [9]. SLIT is a protein secreted by glial cells that regulates cell migration, axonal guidance and axonal branching [10], whereas the TRK receptor accelerates neural growth factor (NGF)-induced differentiation pathways in the CNS [11]. TRK receptors are a family of three tyrosine kinases, which can be activated by neurotrophins active in the brain. SLITRK proteins have
Using rare mutations to unlock the secrets of complex disease
It is clear that rare mutations in small subsets of patients with complex disorders can identify pathways for disease pathogenesis. In this respect, Abelson et al., parallels a report on OCD in which Ozaki et al. [17] found an uncommon coding region mutation (Ile425Val) in the gene encoding the serotonin transporter (SERT) present in seven members of one family. Six of the seven had OCD in addition to other comorbidities (Asperger, social phobia, anorexia nervosa, tic disorders, alcohol and/or
Concluding remarks
Complex disorders continue to present a monumental challenge for gene discovery. Breakthroughs, such as that discovered by Abelson et al., can lead to new models for neurodevelopmental disorders, but current replication efforts and future research will tell the whole story.
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Cited by (11)
The Genetics of Obsessive‐Compulsive Disorder and Tourette Syndrome: An Epidemiological and Pathway‐Based Approach for Gene Discovery
2010, Journal of the American Academy of Child and Adolescent PsychiatryCitation Excerpt :I425V, for example, is a SERT rare variant identified in two independent families and is associated with a complex neuropsychiatric phenotype that includes OCD and autistic traits (below and Table S1, available online). Although it is acknowledged that rare variants will not ultimately explain a large proportion of cases, it can provide a window into biological mechanisms for the disorder.34 GWAS, the mapping of genomes using dense marker sets by contrasting dense gene maps in cases and controls, pose the promise of identifying common risk alleles.
Movement disorders phenomenology: An office-based approach
2020, Movement Disorders Phenomenology: An Office-Based ApproachStereotactic radiofrequency thermocoagulation application in the anterior limbs of patients’ internal capsules in treating intractable tic disorders
2020, International Journal of HyperthermiaSlitrk missense mutations associated with neuropsychiatric disorders distinctively impair slitrk trafficking and synapse formation
2016, Frontiers in Molecular Neuroscience