RIT2 Polymorphisms: Is There a Differential Association?

Emamalizadeh, Babak; Jamshidi, Javad; Movafagh, Abolfazl; Ohadi, Mina; Khaniani, Mahmoud Shekari; Kazeminasab, Somayeh; Biglarian, Akbar; Taghavi, Shaghayegh; Motallebi, Marzieh; Fazeli, Atena; Ahmadifard, Azadeh; Shahidi, Gholam Ali; Petramfar, Peyman; Shahmohammadibeni, Neda; Dadkhah, Tahereh; Khademi, Ehteram; Tafakhori, Abbas; Khaligh, Ali; Safaralizadeh, Tannaz; Kowsari, Ali; Mirabzadeh, Arash; Zarneh, Amir Ehtesham Shafiei; Khorrami, Mehdi; Shokraeian, Parasto; Banavandi, Mohammad Javad Soltani; Lima, Behnam Safarpour; Andarva, Monavvar; Alehabib, Elham; Atakhorrami, Minoo; Darvish, Hossein

doi:10.1007/s12035-016-9815-4

Cited by 34 publications

(33 citation statements)

References 53 publications

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“…Recent findings of a link between the low-frequency alleles at the extreme short and long ends of "exceptionally long" STRs with human disorders [5][6][7] Fig. 8.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously reported that approximately 2% of the human protein-coding genes contain STRs of ≥6 repeats in the critical core promoter region [3]. Preliminary findings indicate that expansion of a number of these STRs may be linked to adaptive evolutionary processes in human, and also endure the burden of certain human disorders such as schizophrenia, bipolar disorder, and Alzheimer's disease [4][5][6][7].…”

Section: Introductionmentioning

confidence: 92%

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Natural Selection at the NHLH2 Core Promoter Exceptionally Long CA-Repeat in Human and Disease-Only Genotypes in Late-Onset Neurocognitive Disorder

Afshar¹,

Adelirad²,

Kowsari³

et al. 2020

Gerontology

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Background: Approximately 2% of the human core promoter short tandem repeats (STRs) reach lengths of ≥6 repeats, which may in part be a result of adaptive evolutionary processes and natural selection. A single-exon transcript of the human nescient helix loop helix 2 (NHLH2) gene is flanked by the longest CA-repeat detected in a human protein-coding gene core promoter (Ensembl transcript ID: ENST00000369506.1). NHLH2 is involved in several biological and pathological pathways, such as motivated exercise, obesity, and diabetes. Methods: The allele and genotype distribution of the NHLH2 CA-repeat were investigated by sequencing in 655 Iranian subjects, consisting of late-onset neurocognitive disorder (NCD) as a clinical entity (n = 290) and matched controls (n = 365). The evolutionary trend of the CA-repeat was also studied across vertebrates. Results: The allele range was between 9 and 25 repeats in the NCD cases, and 12 and 24 repeats in the controls. At the frequency of 0.56, the 21-repeat allele was the predominant allele in the controls. While the 21-repeat was also the predominant allele in the NCD patients, we detected significant decline of the frequency (p < 0.0001) and homozygosity (p < 0.006) of this allele in this group. Furthermore, 12 genotypes were detected across 16 patients (5.5% of the entire NCD sample) and not in the controls (disease-only genotypes; p < 0.0003), consisting of at least one extreme allele. The extreme alleles were at 9, 12, 13, 18, and 19 repeats (extreme short end), and 23, 24, and 25 repeats (extreme long end), and their frequencies ranged between 0.001 and 0.04. The frequency of the 21-repeat allele significantly dropped to 0.09 in the disease-only genotype compartment (p <

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“…Recent findings of a link between the low-frequency alleles at the extreme short and long ends of "exceptionally long" STRs with human disorders [5][6][7] Fig. 8.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 92%

Natural Selection at the NHLH2 Core Promoter Exceptionally Long CA-Repeat in Human and Disease-Only Genotypes in Late-Onset Neurocognitive Disorder

Afshar¹,

Adelirad²,

Kowsari³

et al. 2020

Gerontology

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“…Recent GWAS studies reported Rit2 as a risk allele for several DA-associated disorders, including PD, ET, ASD, schizophrenia, and bipolar disorder [14]. The link between Rit2 expression and schizophrenia is particularly interesting.…”

Section: Rit2 Expression Increases Throughout Postnatal Development Amentioning

confidence: 99%

“…The link between Rit2 expression and schizophrenia is particularly interesting. A recent report examining genome-wide human 5' short tandem repeats (STRs) found that the RIT2 locus has among the longest GA-STRs in humans, at 11 repeats, and that increased STR length drives increased Rit2 expression [14]. Moreover, a 5/5 STR Rit2 variant was identified in a proband with profound early onset psychoses, raising the possibility that decreased Rit2 expression may be linked to schizophrenia.…”

Section: Rit2 Expression Increases Throughout Postnatal Development Amentioning

confidence: 99%

“…The neuronal, Ras-like GTPase, Rit2 (aka: Rin, ras-like in neurons), is enriched in DANs [8] and is required for NGF-mediated MAP kinase activation in neuroendocrine cells [9,10]. Multiple genome-wide association studies (GWAS) identified Rit2 in several DA-related disorders, including PD [11], ASD [12], essential tremor, schizophrenia, and bipolar disorder [13][14][15]. We previously demonstrated that Rit2 binds directly to the presynaptic, cocaine-sensitive DAT, and that Rit2 activity is required for PKC-stimulated DAT endocytosis in cell lines [16].…”

Section: Introductionmentioning

confidence: 99%

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Conditional, inducible gene silencing in dopamine neurons reveals a sex-specific role for Rit2 GTPase in acute cocaine response and striatal function

Sweeney

Kearney

Fagan

et al. 2019

Neuropsychopharmacol.

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Dopamine (DA) signaling is critical for movement, motivation, and addictive behavior. The neuronal GTPase, Rit2, is enriched in DA neurons (DANs), binds directly to the DA transporter (DAT), and is implicated in several DA-related neuropsychiatric disorders. However, it remains unknown whether Rit2 plays a role in either DAergic signaling and/or DA-dependent behaviors. Here, we leveraged the TET-OFF system to conditionally silence Rit2 in Pitx3 IRES2-tTA mouse DANs. Following DAergic Rit2 knockdown (Rit2-KD), mice displayed an anxiolytic phenotype, with no change in baseline locomotion. Further, males exhibited increased acute cocaine sensitivity, whereas DAergic Rit2-KD suppressed acute cocaine sensitivity in females. DAergic Rit2-KD did not affect presynaptic TH and DAT protein levels in females, nor was TH was affected in males; however, DAT was significantly diminished in males. Paradoxically, despite decreased DAT levels in males, striatal DA uptake was enhanced, but was not due to enhanced DAT surface expression in either dorsal or ventral striatum. Finally, patch recordings in nucleus accumbens (NAcc) medium spiny neurons (MSNs) revealed reciprocal changes in spontaneous EPSP (sEPSP) frequency in male and female D1+ and D2+ MSNs following DAergic Rit2-KD. In males, sEPSP frequency was decreased in D1+, but not D2+, MSNs, whereas in females sEPSP frequency decreased in D2+, but not D1+, MSNs. Moreover, DAergic Rit2-KD abolished the ability of cocaine to reduce sEPSP frequency in D1+, but not D2+, male MSNs. Taken together, our studies are among the first to acheive AAV-mediated, conditional and inducible DAergic knockdown in vivo. Importantly, our results provide the first evidence that DAergic Rit2 expression differentially impacts striatal function and DA-dependent behaviors in males and females.

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Molecular Genetics of Essential Tremor

Houle

Rouleau

2018

Encyclopedia of Life Sciences

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Essential tremor (ET) is a movement disorder characterised by involuntary and rhythmic shaking, especially in the hands. The primary symptom associated with ET is an action tremor, which occurs with the purposeful use of a body part, like the hand. ET has a strong genetic component as 50–70% of cases have a familial history where transmission is typically autosomal dominant. The high rate of misdiagnosis, which is in part due to the absence of biomarkers, imaging or genetic markers, complicates the identification of genetic risk factors. Another challenging aspect is the overlapping clinical and pathological features between ET and Parkinson's disease (PD), along with the evidence of increased odds of developing PD when affected by ET. Decades of research have identified several ET loci and candidate genes, albeit replication studies, when available, yielded mixed results, and in most cases, evidence supporting variant causality remains poor. Nonetheless, these associations provide valuable insights into the complexity of the genetics underlying the disorder. Key Concepts Essential tremor is a neurological disorder characterised by involuntary and rhythmic shaking. The causes of essential tremor are unknown. Strong evidence supports high heritability for essential tremor. Decades of research have suggested multiple loci and genes associated with the disorder. Few of these genetic associations have been replicated in independent cohorts.

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RIT2 Polymorphisms: Is There a Differential Association?

Cited by 34 publications

References 53 publications

Natural Selection at the NHLH2 Core Promoter Exceptionally Long CA-Repeat in Human and Disease-Only Genotypes in Late-Onset Neurocognitive Disorder

Natural Selection at the NHLH2 Core Promoter Exceptionally Long CA-Repeat in Human and Disease-Only Genotypes in Late-Onset Neurocognitive Disorder

Conditional, inducible gene silencing in dopamine neurons reveals a sex-specific role for Rit2 GTPase in acute cocaine response and striatal function

Molecular Genetics of Essential Tremor

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