<i>Sapap3</i> and pathological grooming in humans: Results from the OCD collaborative genetics study

Bienvenu, O. Joseph; Wang, Y.; Shugart, Yin Yao; Welch, Jeffrey M.; Grados, Marco A.; Fyer, Abby J.; Rauch, Scott L.; McCracken, James T.; Rasmussen, Steven A.; Murphy, Dennis L.; Cullen, Bernadette; Valle, David; Hoehn‐Saric, Rudolf; Greenberg, Benjamin D.; Pinto, Anthony; Knowles, James A.; Piacentini, John; Pauls, David L.; Liang, Kung‐Yee; Willour, Virginia L.; Riddle, Mark A.; Samuels, Jack; Feng, Guoping; Nestadt, Gerald

doi:10.1002/ajmg.b.30897

Cited by 192 publications

(143 citation statements)

References 62 publications

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“…For example, human genetic associations for grooming disorders in OCD are related to a gene, SAPAP3, whose expression is enriched in the striatum (Bienvenu et al, 2008). Mice that lack the striatal-enriched, dendritically expressed, postsynaptic density scaffolding protein DLGAP3 (SAPAP3) show excessive grooming, which, as in the case of OCD in humans, can be ameliorated with SSRIs (Welch et al, 2007).…”

Section: Future Research Directionsmentioning

confidence: 99%

Neurogenetics and Pharmacology of Learning, Motivation, and Cognition

Frank

Fossella

2010

Neuropsychopharmacol

172

167

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Many of the individual differences in cognition, motivation, and learningFand the disruption of these processes in neurological conditionsFare influenced by genetic factors. We provide an integrative synthesis across human and animal studies, focusing on a recent spate of evidence implicating a role for genes controlling dopaminergic function in frontostriatal circuitry, including COMT, DARPP-32, DAT1, DRD2, and DRD4. These genetic effects are interpreted within theoretical frameworks developed in the context of the broader cognitive and computational neuroscience literature, constrained by data from pharmacological, neuroimaging, electrophysiological, and patient studies. In this framework, genes modulate the efficacy of particular neural computations, and effects of genetic variation are revealed by assays designed to be maximally sensitive to these computations. We discuss the merits and caveats of this approach and outline a number of novel candidate genes of interest for future study.

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Section: Future Research Directionsmentioning

confidence: 99%

Neurogenetics and Pharmacology of Learning, Motivation, and Cognition

Frank

Fossella

2010

Neuropsychopharmacol

172

167

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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.…”

mentioning

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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“…Finally, as noted in our article 5 and in the accompanying editorial by Gur, 6 while we modeled sociodemographic factors, cannabis use, and common mental disorders as confounders, they could also be mediators. Begemann and colleagues highlight how the same ambiguity arises with childhood trauma.…”

Section: Childhood Trauma As a Neglected Factor In Psychotic Experienmentioning

confidence: 97%

Childhood Trauma as a Neglected Factor in Psychotic Experiences and Cognitive Functioning

Begemann

Sommer

2016

JAMA Psychiatry

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of inherent limitations, detailed in our publication, cautious interpretation of the findings is suggested.In this context, use of estrogen-based therapies for prevention or treatment of postmenopausal depression in the general population, on the basis of our findings, was clearly not recommended. This option is precluded owing to known adverse effects of currently available hormone therapy regimens and uncertainties regarding appropriate combination of estrogens and progestogens in postmenopausal women with intact uterus. However, owing to its potential clinical implication, we considered of interest and accordingly highlighted, the 2-fold increased depression risk of women with premature ovarian insufficiency (menopause at <40 years). These women represent only 1% of the female population but comprise a high-risk group for additional postmenopausal diseases; therefore, they deserve to be appropriately followed up for early recognition and evaluation of depressive symptoms. Hormone therapy has been recommended for treatment of estrogen deficiency symptoms in this group, 5 albeit its effect on preventing depression should be explored following our findings. All in all, our meta-analysis points to novel research questions regarding the effect of the cumulative lifetime sex hormone exposure on nervous system and mental health and the sustained neuroprotective and antidepressive properties of estrogens or progesterone.

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Sapap3 and pathological grooming in humans: Results from the OCD collaborative genetics study

Cited by 192 publications

References 62 publications

Neurogenetics and Pharmacology of Learning, Motivation, and Cognition

Neurogenetics and Pharmacology of Learning, Motivation, and Cognition

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

Childhood Trauma as a Neglected Factor in Psychotic Experiences and Cognitive Functioning

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