Family‐based genetic association study of <i>DLGAP3</i> in Tourette Syndrome

Crane, Jacquelyn; Fagerness, Jesen; Osiecki, Lisa; Gunnell, B.; Stewart, S. Evelyn; Pauls, David L.; Scharf, Jeremiah M.; Heutink, Peter

doi:10.1002/ajmg.b.31134

Cited by 65 publications

(46 citation statements)

References 28 publications

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“…Seventy-four additional ancestry-informative markers (AIMs) were also genotyped to control for population substructure (Table S2). Genotyping was performed using primer extension and mass spectrophotometry (Sequenom, San Diego, CA, USA) as previously described (Crane et al 2011). …”

Section: Methodsmentioning

confidence: 99%

Genetic association signal near NTN4 in Tourette syndrome

Paschou

Gerber

et al. 2014

Annals of Neurology

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Tourette Syndrome (TS) is a neurodevelopmental disorder with a complex genetic etiology. Through an international collaboration, we genotyped 42 single nucleotide polymorphisms (SNPs)(p<10−3) from the recent TS genome-wide association study (GWAS) in 609 independent cases and 610 ancestry-matched controls. Only rs2060546 on chromosome 12q22 (p=3.3×10−4) remained significant after Bonferroni correction. Meta-analysis with the original GWAS yielded the strongest association to date (p=5.8×10−7). Although its functional significance is unclear, rs2060546 lies closest to NTN4, an axon guidance molecule expressed in developing striatum. Risk score analysis significantly predicted case/control status (p=0.042), suggesting that many of these variants are true TS risk alleles.

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Section: Methodsmentioning

confidence: 99%

Genetic association signal near NTN4 in Tourette syndrome

Paschou

Gerber

et al. 2014

Annals of Neurology

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“…Much attention has been paid to dopaminergic candidates, and there is evidence of a significant association between TS and a dopamine transporter polymorphism (DAT1 Ddel) (Yoon et al, 2007b). Several recent candidate genes have included: a heterozygous loss of function mutation in L-histidine decarboxylase, which encodes the rate limiting enzyme in histamine biosynthesis (Ercan-Sencicek et al, 2010); functional variations of the SLITRK1 gene, with homology to a known axon guidance molecule (Scharf et al, 2008); and DLGAP3, a postsynaptic scaffolding protein highly expressed in striatal glutamatergic synapses (Crane et al, 2011).…”

Section: Etiologymentioning

confidence: 99%

Neurobiology of Tourette Syndrome: Current Status and Need for Further Investigation: Table 1.

Felling¹,

Singer²

2011

J. Neurosci.

204

116

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Tourette syndrome (TS) is a common, chronic neuropsychiatric disorder characterized by the presence of fluctuating motor and phonic tics. The typical age of onset is ϳ5-7 years, and the majority of children improve by their late teens or early adulthood. Affected individuals are at increased risk for the development of various comorbid conditions, such as obsessive-compulsive disorder, attention deficit hyperactivity disorder, school problems, depression, and anxiety. There is no cure for tics, and symptomatic therapy includes behavioral and pharmacological approaches. Evidence supports TS being an inherited disorder; however, the precise genetic abnormality remains unknown. Pathologic involvement of cortico-striatal-thalamo-cortical (CSTC) pathways is supported by neurophysiological, brain imaging, and postmortem studies, but results are often confounded by small numbers, age differences, severity of symptoms, comorbidity, use of pharmacotherapy, and other factors. The primary site of abnormality remains controversial. Although numerous neurotransmitters participate in the transmission of messages through CSTC circuits, a dopaminergic dysfunction is considered a leading candidate. Several animal models have been used to study behaviors similar to tics as well as to pursue potential pathophysiological deficits. TS is a complex disorder with features overlapping a variety of scientific fields. Despite description of this syndrome in the late 19th century, there remain numerous unanswered neurobiological questions.In the 1880's, Georges Gilles de la Tourette published a two-part article in which he emphasized differences between tics and chorea. Although many of the descriptions about the disorder, which now bears his name [Tourette syndrome (TS)], have been revised, his belief that tics are a neurological movement disorder and not a psychiatric condition persists to the present (Goetz and Klawans, 1982). Nevertheless, despite multiple advances and widespread acceptance of TS being a biological disorder, the precise etiology and underlying pathophysiological mechanisms remain unknown. The goals of the present review are to briefly describe the clinical phenomenology of TS and related tic disorders, to review current information on genetic and neurobiological mechanisms, and to identify areas in need of further investigation.

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“…In addition to orchestrating PSD formation, these scaffold proteins also serve to control the trafficking and clustering of receptors on the plasma membranes and to interface with actin cytoskeletons at synapses (15,18,19). Mutations of DLGs, SAPAP, and Shank have been found to cause or associate with various psychiatric disorders, including autism spectrum disorder (ASD), depression, and schizophrenia (20)(21)(22)(23)(24)(25)(26)(27)(28), further supporting the importance of these proteins in normal brain development and functions.…”

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confidence: 96%

A binding site outside the canonical PDZ domain determines the specific interaction between Shank and SAPAP and their function

Zeng

Shang

Guo

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Shank and SAPAP (synapse-associated protein 90/postsynaptic density-95-associated protein) are two highly abundant scaffold proteins that directly interact with each other to regulate excitatory synapse development and plasticity. Mutations of SAPAP, but not other reported Shank PDZ domain binders, share a significant overlap on behavioral abnormalities with the mutations of Shank both in patients and in animal models. The molecular mechanism governing the exquisite specificity of the Shank/SAPAP interaction is not clear, however. Here we report that a sequence preceding the canonical PDZ domain of Shank, together with the elongated PDZ BC loop, form another binding site for a sequence upstream of the SAPAP PDZ-binding motif, leading to a several hundred-fold increase in the affinity of the Shank/SAPAP interaction. We provide evidence that the specific interaction afforded by this newly identified site is required for Shank synaptic targeting and the Shank-induced synaptic activity increase. Our study provides a molecular explanation of how Shank and SAPAP dosage changes due to their gene copy number variations can contribute to different psychiatric disorders.Shank | SAPAP | PDZ | synapse | specific interaction P ostsynaptic density (PSD) at excitatory synapses refers to disk-shaped, densely packed mega-protein assemblies located beneath postsynaptic membranes (1-5). A set of highly abundant scaffold proteins, including DLGs (disc large proteins including PSD-95, PSD-93, and SAP102), SAPAP (synapse-associated protein 90/postsynaptic density-95-associated protein; also known as GKAP or DLGAP), and Shank, are known to be critical for the formation, stability, and neuronal activity-dependent dynamic regulations of . In addition to orchestrating PSD formation, these scaffold proteins also serve to control the trafficking and clustering of receptors on the plasma membranes and to interface with actin cytoskeletons at synapses (15,18,19). Mutations of DLGs, SAPAP, and Shank have been found to cause or associate with various psychiatric disorders, including autism spectrum disorder (ASD), depression, and schizophrenia (20-28), further supporting the importance of these proteins in normal brain development and functions.Electron and superresolution light microscopy imaging studies (4,5,18,(29)(30)(31)(32) have revealed that proteins in PSDs form distinct layers along the axodendritic axis of synapses with a sequential order of membrane-spanning glutamate receptors and cell adhesion molecules, DLGs, the SAPAP and Shank scaffolds, and actin cytoskeletons. Such a distinct layered structure in PSDs depends critically on the specific interactions between the scaffold proteins. For example, the phosphorylation-dependent interaction between DLG GK domain and the N-terminal repeating sequences of SAPAP positions SAPAP beneath DLGs (33), and the interaction between the SAPAP PDZ-binding motif (PBM) and Shank PDZ domain functions to place Shank at a deeper layer in PSD (7).The critical roles of the PSD scaffold proteins in norma...

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Family‐based genetic association study of DLGAP3 in Tourette Syndrome

Cited by 65 publications

References 28 publications

Genetic association signal near NTN4 in Tourette syndrome

Genetic association signal near NTN4 in Tourette syndrome

Neurobiology of Tourette Syndrome: Current Status and Need for Further Investigation: Table 1.

A binding site outside the canonical PDZ domain determines the specific interaction between Shank and SAPAP and their function

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