REVERSE phenotyping—Can the phenotype <i>following constitutive Tph2 gene inactivation in mice</i> be transferred to children and adolescents with and without adhd?

Akhrif, Atae; Roy, Arunima; Peters, Katharina; Lesch, Klaus‐Peter; Romanos, Marcel; Schmitt-Böhrer, Angelika G.; Neufang, Susanne

doi:10.1002/brb3.2054

Cited by 3 publications

(2 citation statements)

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“…TPH2 -deficient mice show anxiety-like behavior ( Waider et al, 2011 ). The Tph2 null mutant mouse mimics the TPH2 G-703T phenotype in humans ( Akhrif et al, 2021 ). High tyrosine levels can decrease TPH2 activity and tyrosinemia type 1 presents with ADHD symptoms as shown in 8 Norwegian children ( Barone et al, 2020 ).…”

Section: Resultsmentioning

confidence: 99%

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Attention-deficit/hyperactive disorder updates

Kessi

Duan

Xiong

et al. 2022

Front. Mol. Neurosci.

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BackgroundAttention-deficit/hyperactive disorder (ADHD) is a neurodevelopmental disorder that commonly occurs in children with a prevalence ranging from 3.4 to 7.2%. It profoundly affects academic achievement, well-being, and social interactions. As a result, this disorder is of high cost to both individuals and society. Despite the availability of knowledge regarding the mechanisms of ADHD, the pathogenesis is not clear, hence, the existence of many challenges especially in making correct early diagnosis and provision of accurate management.ObjectivesWe aimed to review the pathogenic pathways of ADHD in children. The major focus was to provide an update on the reported etiologies in humans, animal models, modulators, therapies, mechanisms, epigenetic changes, and the interaction between genetic and environmental factors.MethodsReferences for this review were identified through a systematic search in PubMed by using special keywords for all years until January 2022.ResultsSeveral genes have been reported to associate with ADHD: DRD1, DRD2, DRD4, DAT1, TPH2, HTR1A, HTR1B, SLC6A4, HTR2A, DBH, NET1, ADRA2A, ADRA2C, CHRNA4, CHRNA7, GAD1, GRM1, GRM5, GRM7, GRM8, TARBP1, ADGRL3, FGF1, MAOA, BDNF, SNAP25, STX1A, ATXN7, and SORCS2. Some of these genes have evidence both from human beings and animal models, while others have evidence in either humans or animal models only. Notably, most of these animal models are knockout and do not generate the genetic alteration of the patients. Besides, some of the gene polymorphisms reported differ according to the ethnic groups. The majority of the available animal models are related to the dopaminergic pathway. Epigenetic changes including SUMOylation, methylation, and acetylation have been reported in genes related to the dopaminergic pathway.ConclusionThe dopaminergic pathway remains to be crucial in the pathogenesis of ADHD. It can be affected by environmental factors and other pathways. Nevertheless, it is still unclear how environmental factors relate to all neurotransmitter pathways; thus, more studies are needed. Although several genes have been related to ADHD, there are few animal model studies on the majority of the genes, and they do not generate the genetic alteration of the patients. More animal models and epigenetic studies are required.

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Section: Resultsmentioning

confidence: 99%

“…Tph2 null mutant mouse reproduces the TPH2 G-703T-dependent ADHD phenotype in humans (Akhrif et al, 2021).…”

Section: Tph2 Nonementioning

confidence: 96%

Attention-deficit/hyperactive disorder updates

Kessi

Duan

Xiong

et al. 2022

Front. Mol. Neurosci.

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REVERSE phenotyping—Can the phenotype following constitutive Tph2 gene inactivation in mice be transferred to children and adolescents with and without adhd?

et al. 2021

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Introduction Experimental models of neuropsychiatric disorders, for example, ADHD, are used to mimic specific phenotypic traits of a complex human disorder. However, it remains unresolved to what extent the animal phenotype reflects the specific human trait. The null mutant mouse of the serotonin‐synthesizing tryptophan hydroxylase‐2 (Tph2‐/‐) gene has been proposed as experimental model for ADHD with high face validity for impulsive, aggressive, and anxious behaviors. To validate this ADHD‐like model, we examined the Tph2‐/‐ phenotype in humans when considering allelic variation of TPH2 function (“reverse phenotyping”). Methods 58 participants (6 females, 8–18 years) were examined, of whom 32 were diagnosed with ADHD. All participants were phenotyped for impulsivity, aggression, and anxiety using questionnaires, behavioral tests, and MRI scanning while performing the 4‐choice serial reaction time task. Additionally, participants were genotyped for the TPH2 G‐703T (rs4570625) polymorphism. To analyze the relation between TPH2 G‐703T variants and the impulsive/aggressive/anxious phenotype, mediation analyses were performed using behavioral and MRI data as potential mediators. Results We found that the relation between TPH2 G‐703T and aggression as part of the reverse Tph2‐/‐ phenotype was mediated by structure and function of the right middle and inferior frontal gyrus. Conclusion At the example of trait aggression, our results support the assumption that the Tph2 null mutant mouse reflects the TPH2 G‐703T‐dependent phenotype in humans. Additionally, we conclude that “reverse phenotyping” is a promising method to validate experimental models and human findings for refined analysis of disease mechanisms.

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