Evidence that ITGB3 promoter variants increase serotonin blood levels by regulating platelet serotonin transporter trafficking

Gabriele, Stefano; Canali, Marco; Lintas, Carla; Sacco, Roberto; Tirindelli, Maria Cristina; Ricciardello, Arianna; Persico, Antonio M.

doi:10.1093/hmg/ddy421

Cited by 14 publications

(12 citation statements)

References 58 publications

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“…Very interestingly, an animal study on communal nesting (CN), a highly stimulating early social enrichment for rodents, showed that CN results in significant differences in social behaviors later in life and is associated with higher NGF and BDNF levels in the brain of adult mice (Branchi et al, 2006). Additional signaling networks that are also implicated in social behavioral deficits in autism include AVB3-INTEGRIN (Schuch et al, 2014; Dohn et al, 2017; Gabriele et al, 2019), PI3K-ERBB2/4 (Pinto et al, 2010), SEMA3A-PKA, and REELIN signaling (De Rubeis et al, 2014; Lammert et al, 2017; Stessman et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Affected Sib-Pair Analyses Identify Signaling Networks Associated With Social Behavioral Deficits in Autism

et al. 2019

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Autism spectrum disorders (ASDs) are characterized by deficits in three core behavioral domains: reciprocal social interactions, communication, and restricted interests and/or repetitive behaviors. Several hundreds of risk genes for autism have been identified, however, it remains a challenge to associate these genes with specific core behavioral deficits. In multiplex autism families, affected sibs often show significant differences in severity of individual core phenotypes. We hypothesize that a higher mutation burden contributes to a larger difference in the severity of specific core phenotypes between affected sibs. We tested this hypothesis on social behavioral deficits in autism. We sequenced synaptome genes (n = 1,886) in affected male sib-pairs (n = 274) in families from the Autism Genetics Research Exchange (AGRE) and identified rare (MAF ≤ 1%) and predicted functional variants. We selected affected sib-pairs with a large (≥10; n = 92 pairs) or a small (≤4; n = 108 pairs) difference in total cumulative Autism Diagnostic Interview-Revised (ADI-R) social scores (SOCT_CS). We compared burdens of unshared variants present only in sibs with severe social deficits and found a higher burden in SOCT_CS≥10 compared to SOCT_CS ≤ 4 (SOCT_CS≥10: 705.1 ± 16.2; SOCT_CS ≤ 4, 668.3 ± 9.0; p = 0.025). Unshared SOCT_CS≥10 genes only in sibs with severe social deficits are significantly enriched in the SFARI gene set. Network analyses of these genes using InWeb_IM, molecular signatures database (MSigDB), and GeNetMeta identified enrichment for phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) (Enrichment Score [eScore] p value = 3.36E−07; n = 8 genes) and Nerve growth factor (NGF) (eScore p value = 8.94E−07; n = 9 genes) networks. These studies support a key role for these signaling networks in social behavioral deficits and present a novel approach to associate risk genes and signaling networks with core behavioral domains in autism.

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Section: Discussionmentioning

confidence: 99%

Affected Sib-Pair Analyses Identify Signaling Networks Associated With Social Behavioral Deficits in Autism

et al. 2019

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“…Numerous platelets are eventually linked by such fibrinogen bridges, resulting in a platelet plug . As mentioned above, the β‐chain of the αIIbβ3 receptor is encoded by ITGB3 and variants for this gene have been associated with elevated blood 5‐HT levels in ASD . The β3‐subunit associates with αIIb to form the integrin αIIbβ3 in platelets, and with αv to form the integrin αvβ3 in neurons .…”

Section: Platelet Activation Receptor αIibβ3 and Autismmentioning

confidence: 99%

“…Severe psychomotor retardation was reported in only a single patient with Glanzmann thrombasthenia in combination with tuberous sclerosis, which is a multisystemic disorder, sometimes presenting with ASD . Interestingly, a recent study showed that a variant in the ITGB3 gene promoter is associated with enhanced promoter activity in megakaryocytes, higher β3‐subunit expression in platelets, enhanced expression of SERT on the plasma membrane, and elevated 5‐HT levels in blood from ASD cases . This would mean that ASD is not associated with inactivating but rather GOF variants in ITGB3 , probably explaining the absence of obvious autism phenotypes in patients with Glanzmann thrombasthenia.…”

Section: Platelet Activation Receptor αIibβ3 and Autismmentioning

confidence: 99%

“…61,62 As mentioned above, the β-chain of the αIIbβ3 receptor is encoded by ITGB3 and variants for this gene have been associated with elevated blood 5-HT levels in ASD. 57,63,64 The β3-subunit associates with αIIb to form the integrin αIIbβ3 in platelets, and with αv to form the integrin αvβ3 in neurons. 65 In platelets, activated integrin αIIbβ3 interacts directly with the C-terminus of SERT and enhances the externalization and function of SERT.…”

Section: Platelet Activation Receptor αIibβ3 and Autismmentioning

confidence: 99%

“…70 Interestingly, a recent study showed that a variant in the ITGB3 gene promoter is associated with enhanced promoter activity in megakaryocytes, higher β3-subunit expression in platelets, enhanced expression of SERT on the plasma membrane, and elevated 5-HT levels TA B L E 1 Literature review on serotonin quantifications using blood or blood-derived substances from patients with autism in blood from ASD cases. 63 This would mean that ASD is not associated with inactivating but rather GOF variants in ITGB3, probably explaining the absence of obvious autism phenotypes in patients with Glanzmann thrombasthenia. However, a case report with a GOF variant in ITGB3 was reported with bleeding symptoms and mild thrombocytopenia, but a neurological phenotype was not reported.…”

Section: Platelet Activation Receptor αIibβ3 and Autismmentioning

confidence: 99%

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Blood platelet research in autism spectrum disorders: In search of biomarkers

Padmakumar

Raes

Geet

et al. 2019

Research and Practice in Thrombosis and Haemostasis

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Autism spectrum disorder (ASD) is a clinically heterogeneous neurodevelopmental disorder that is caused by gene‐environment interactions. To improve its diagnosis and treatment, numerous efforts have been undertaken to identify reliable biomarkers for autism. None of them have delivered the holy grail that represents a reproducible, quantifiable, and sensitive biomarker. Though blood platelets are mainly known to prevent bleeding, they also play pivotal roles in cancer, inflammation, and neurological disorders. Platelets could serve as a peripheral biomarker or cellular model for autism as they share common biological and molecular characteristics with neurons. In particular, platelet‐dense granules contain neurotransmitters such as serotonin and gamma‐aminobutyric acid. Molecular players controlling granule formation and secretion are similarly regulated in platelets and neurons. The major platelet integrin receptor αIIbβ3 has recently been linked to ASD as a regulator of serotonin transport. Though many studies revealed associations between platelet markers and ASD, there is an important knowledge gap in linking these markers with autism and explaining the altered platelet phenotypes detected in autism patients. The present review enumerates studies of different biomarkers detected in ASD using platelets and highlights the future needs to bring this research to the next level and advance our understanding of this complex disorder.

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Duloxetine attenuates pain in association with downregulation of platelet serotonin transporter in patients with burning mouth syndrome and atypical odontalgia

Nakamura

Yoshimi

Mouri

et al. 2021

Human Psychopharmacology

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Objective:The aim of this study was evaluation of the association between severity of pain and expression of total or ubiquitinated serotonin transporter (SERT) protein in patients with burning mouth syndrome and atypical odontalgia (BMS/AO), who were treated by duloxetine.Methods: Patients with BMS/AO were assessed for severity of pain using the visual analog scale (VAS), and expression of total and ubiquitinated SERT protein in platelets before (baseline) and 12 weeks after duloxetine-treatment. Results:The expression of total and ubiquitinated SERT protein at baseline in all patients (n = 33) were higher and lower, respectively, compared to those in healthy controls. 12 weeks after duloxetine-treatment, there was no difference in the total SERT protein levels between patients (n = 21) and healthy controls. In the 16 patients who could be measured, mean VAS scores and total SERT protein levels were significantly decreased after the treatment, compared to those at baseline. There was tendency for a positive correlation between total SERT protein levels and VAS scores in these patients. Conclusions:Our findings indicate that duloxetine relieves pain in association with downregulation of platelet SERT expression in patients with BMS/AO.

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Evidence that ITGB3 promoter variants increase serotonin blood levels by regulating platelet serotonin transporter trafficking

Cited by 14 publications

References 58 publications

Affected Sib-Pair Analyses Identify Signaling Networks Associated With Social Behavioral Deficits in Autism

Affected Sib-Pair Analyses Identify Signaling Networks Associated With Social Behavioral Deficits in Autism

Blood platelet research in autism spectrum disorders: In search of biomarkers

Duloxetine attenuates pain in association with downregulation of platelet serotonin transporter in patients with burning mouth syndrome and atypical odontalgia

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