Association of FAAH p.Pro129Thr and COMT p.Ala72Ser with schizophrenia and comorbid substance use through next-generation sequencing: an exploratory analysis

Martínez‐Magaña, José Jaime; Genis‐Mendoza, Alma Delia; González-Covarrubias, Vanessa; Juárez‐Rojop, Isela Esther; Tovilla‐Zárate, Carlos Alfonso; Soberón, Xavier; Lanzagorta, Nuria; Nicolini, Humberto

doi:10.1590/1516-4446-2020-1546

Cited by 2 publications

(2 citation statements)

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“…The g.-275 T allele frequency in patients with schizophrenia was significantly higher than that in healthy controls in “East Asian” and “Total groups” populations in the database gnomAD ( Supplementary Table S3 ; p = 0.020 and p < 0.001, respectively). It is located in untranslated region, but it has been reported that this variant is associated with negative symptoms of schizophrenia ( Martinez-Magana et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

AKR1A1 Variant Associated With Schizophrenia Causes Exon Skipping, Leading to Loss of Enzymatic Activity

et al. 2021

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Schizophrenia is a heterogeneous psychiatric disorder characterized by positive symptoms such as hallucinations and delusions, negative symptoms such as anhedonia and flat affect, and cognitive impairment. Recently, glucuronate (GlucA) levels were reported to be significantly higher in serum of patients with schizophrenia than those in healthy controls. The accumulation of GlucA is known to be related to treatment-resistant schizophrenia, since GlucA is known to promote drug excretion by forming conjugates with drugs. However, the cause of GlucA accumulation remains unclear. Aldo-keto reductase family one member A1 (AKR1A1) is an oxidoreductase that catalyzes the reduction of GlucA. Genetic loss of AKR1A1 function is known to result in the accumulation of GlucA in rodents. Here, we aimed to explore genetic defects in AKR1A1 in patients with schizophrenia, which may result in the accumulation of GlucA. We identified 28 variants of AKR1A1 in patients with schizophrenia and control subjects. In particular, we identified a silent c.753G > A (rs745484618, p. Arg251Arg) variant located at the first position of exon 8 to be associated with schizophrenia. Using a minigene assay, we found that the c.753G > A variant induced exon 8 skipping in AKR1A1, resulting in a frameshift mutation, which in turn led to truncation of the AKR1A1 protein. Using the recombinant protein, we demonstrated that the truncated AKR1A1 completely lost its activity. Furthermore, we showed that AKR1A1 mRNA expression in the whole blood cells of individuals with the c.753G > A variant tended to be lower than that in those without the variants, leading to lower AKR activity. Our findings suggest that AKR1A1 carrying the c.753G > A variant induces exon skipping, leading to a loss of gene expression and enzymatic activity. Thus, GlucA patients with schizophrenia with the c.753G > A variant may show higher GlucA levels, leading to drug-resistant schizophrenia, since drug excretion by GlucA is enhanced.

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Section: Discussionmentioning

confidence: 99%

AKR1A1 Variant Associated With Schizophrenia Causes Exon Skipping, Leading to Loss of Enzymatic Activity

et al. 2021

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“…However, Monteleone and colleagues suggested that the A allele of the 385C/A (rs324420) FAAH polymorphism may predispose schizophrenic patients treated with antipsychotics to obtain a clinically meaningful weight gain [309]. More recently, an association between the variant FAAH p.Pro129Thr with substance use was found in individuals with schizophrenia [310].…”

Section: Clinical Studiesmentioning

confidence: 99%

Molecular Alterations of the Endocannabinoid System in Psychiatric Disorders

Navarro

Gasparyan

Navarrete

et al. 2022

IJMS

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The therapeutic benefits of the current medications for patients with psychiatric disorders contrast with a great variety of adverse effects. The endocannabinoid system (ECS) components have gained high interest as potential new targets for treating psychiatry diseases because of their neuromodulator role, which is essential to understanding the regulation of many brain functions. This article reviewed the molecular alterations in ECS occurring in different psychiatric conditions. The methods used to identify alterations in the ECS were also described. We used a translational approach. The animal models reproducing some behavioral and/or neurochemical aspects of psychiatric disorders and the molecular alterations in clinical studies in post-mortem brain tissue or peripheral tissues were analyzed. This article reviewed the most relevant ECS changes in prevalent psychiatric diseases such as mood disorders, schizophrenia, autism, attentional deficit, eating disorders (ED), and addiction. The review concludes that clinical research studies are urgently needed for two different purposes: (1) To identify alterations of the ECS components potentially useful as new biomarkers relating to a specific disease or condition, and (2) to design new therapeutic targets based on the specific alterations found to improve the pharmacological treatment in psychiatry.

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Association of FAAH p.Pro129Thr and COMT p.Ala72Ser with schizophrenia and comorbid substance use through next-generation sequencing: an exploratory analysis

Cited by 2 publications

References 56 publications

AKR1A1 Variant Associated With Schizophrenia Causes Exon Skipping, Leading to Loss of Enzymatic Activity

AKR1A1 Variant Associated With Schizophrenia Causes Exon Skipping, Leading to Loss of Enzymatic Activity

Molecular Alterations of the Endocannabinoid System in Psychiatric Disorders

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