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![Localization of ADCY5 mutations. (A) Schematic representation of ADCY5 mutations in the gene. Localization of the reported patients' mutations in the exons of ADCY5 gene. (B) Localization of ADCY5 mutations on the domains of the protein. TM, transmembrane domain; C1 and C2, cytoplasmic domains. [Color figure can be viewed at wileyonlinelibrary.com]](publication/351284897/figure/fig2/AS:1023360653873153@1620999601472/Localization-of-ADCY5-mutations-A-Schematic-representation-of-ADCY5-mutations-in-the.png)
Localization of ADCY5 mutations. (A) Schematic representation of ADCY5 mutations in the gene. Localization of the reported patients' mutations in the exons of ADCY5 gene. (B) Localization of ADCY5 mutations on the domains of the protein. TM, transmembrane domain; C1 and C2, cytoplasmic domains. [Color figure can be viewed at wileyonlinelibrary.com]
Source publication
Adenylyl cyclase 5 (ADCY5)‐related phenotypes comprise an expanding disease continuum, but much remains to be understood about the underlying pathogenic mechanisms of the disease. ADCY5‐related disease comprises a spectrum of hyperkinetic disorders involving chorea, myoclonus, and/or dystonia, often with paroxysmal exacerbations. Hypotonia, develop...
Context in source publication
Context 1
... and C2 are brought together to form an ATP-binding site with a catalytic pocket for the hydrolysis of ATP. 33 As illustrated in Figure 3, the majority of the reported mutations are located in C1 and C2 domains, suggesting how they might affect the strength of enzyme-substrate binding or the C1-C2 interaction to form the catalytic pocket. For example, the most common mutation on residue arginine 418 lies in the cytoplasmic domain C1 and replaces a branched positively charged amino acid with the negatively charged amino acid tryptophan, likely affecting the normal formation of the catalytic pocket. ...
Citations
... [5][6][7][8][9][10] Correspondingly, pathogenic variants in genes critical for postsynaptic dopamine receptor signal transduction are associated with dystonia. [11][12][13][14][15] Even without overt gene defects, disruptions in dopamine neurotransmission can cause dystonia, such as tardive dystonia following dopamine receptor antagonist treatment. 16 Compelling evidence for the role of dopamine dysfunction in dystonia is DOPA-responsive dystonia (DRD), a group of childhood-onset dystonias that markedly improve after administration of L-DOPA, the synthetic precursor of dopamine. ...
Striatal dysfunction is implicated in many forms of dystonia, including idiopathic, inherited and iatrogenic dystonias. The striatum is comprised largely of GABAergic spiny projection neurons (SPNs) that are defined by their long-range efferents. Direct SPNs (dSPNs) project to the internal globus pallidus/substantia nigra reticulata whereas indirect pathway SPNs (iSPNs) project to the external pallidum; the concerted activity of both SPN subtypes modulates movement. Convergent results from genetic, imaging and physiological studies in patients suggest that abnormalities of both dSPNs and iSPNs contribute to the expression of dystonia, but the molecular adaptations underlying these abnormalities are not known. Here we provide a comprehensive analysis of SPN cell-type specific molecular signatures in a model of DOPA-responsive dystonia (DRD mice), which is caused by gene defects that reduce dopamine neurotransmission, resulting in dystonia that is specifically associated with striatal dysfunction. Individually profiling the translatome of dSPNs and iSPNs using translating ribosome affinity purification with RNA-seq revealed hundreds of differentially translating mRNAs in each SPN subtype in DRD mice, yet there was little overlap between the dysregulated genes in dSPNs and iSPNs. Despite the paucity of shared adaptations, a disruption in glutamatergic signaling was predicted for both dSPNs and iSPNs. Indeed, we found that both AMPA and NMDA receptor-mediated currents were enhanced in dSPNs but diminished in iSPNs in DRD mice. The pattern of mRNA dysregulation was specific to dystonia as the adaptations in DRD mice were distinct from those in parkinsonian mice where the dopamine deficit occurs in adults, suggesting that the phenotypic outcome is dependent on both the timing of the dopaminergic deficit and the SPN-specific adaptions. We leveraged the unique molecular signatures of dSPNs and iSPNs in DRD mice to identify biochemical mechanisms that may be targets for therapeutics, including LRRK2 inhibition. Administration of the LRRK2 inhibitor MLi-2 ameliorated the dystonia in DRD mice suggesting a novel target for therapeutics and demonstrating that the delineation of cell-type specific molecular signatures provides a powerful approach to revealing both CNS dysfunction and therapeutic targets in dystonia.
... We were able to demonstrate that treatment with the purine derivatives caffeine, theophylline, and istradefylline reduced ADCY5-catalyzed cAMP production in cell lines overexpressing wild-type and mutant ADCY5. The most pronounced effects on cAMP reduction were observed in ADCY5 R418W mutant cells 13 , a mutation found in the majority of individuals with ADCY5-related dyskinesia 14 . Following these findings, a slow-release theophylline formulation was administered to a preschool-aged patient with ADCY5-related dyskinesia, resulting in a striking improvement of symptoms, surpassing the effects of caffeine that had previously been administered to the same patient. ...
Background
ADCY5-related dyskinesia is a rare disorder caused by mutations in the ADCY5 gene resulting in abnormal involuntary movements. Currently, there are no standardized guidelines to treat this condition.
Objectives
The aim of this study is to evaluate the efficacy of theophylline administration in improving symptoms and quality of life in patients with ADCY5-related dyskinesia.
Methods
A retrospective study was conducted involving 12 patients (aged 2-34 years) with ADCY5-related dyskinesia. Participants completed a questionnaire about theophylline administration, including dosage, improvement of symptoms, adverse effects, and changes in quality of life. Data were analyzed for reported efficacy and side effects.
Results
Theophylline administration demonstrated substantial efficacy, with 92% (11 out of 12) of patients reporting significant improvements in their movement disorders. The average improvement score was 7.0 (± 1.9) on a 10-point scale. Notable improvements included reductions in severity and frequency of episodes, improved gait, more independent mobility, psycho-social well-being, and quality of sleep. Adverse effects were reported by 6 patients, including dystonia, speech worsening, headaches, nausea, impaired sleep, and agitation.
Conclusions
Theophylline shows substantial promise as a treatment option for ADCY5-related dyskinesia, improving various aspects of patients’ quality of life and movement disorder symptoms. Further research is needed to optimize dosing, to understand long-term effects, and to explore combinational drug therapies. Despite the small cohort size and the retrospective nature of this study, the results support theophylline administration to decrease dyskinetic movements and enhance overall quality of life in patients.
... The clinical phenotype includes variable combinations of hyperkinetic movements, most commonly focal or generalized chorea, dystonia, and myoclonus. Choreic movements also classically involve the facial muscles (perioral and periorbital), with episodic exacerbations, variability in severity, and a duration from minutes to hours, observed more frequently upon night-time awakening, with subsequent delayed sleep [18]. ...
Chorea is a hyperkinetic movement disorder frequently observed in the pediatric population, and, due to advancements in genetic techniques, an increasing number of genes have been associated with this disorder. In genetic conditions, chorea may be the primary feature of the disorder, or be part of a more complex phenotype characterized by epileptic encephalopathy or a multisystemic syndrome. Moreover, it can appear as a persistent disorder (chronic chorea) or have an episodic course (paroxysmal chorea). Managing chorea in childhood presents challenges due to its varied clinical presentation, often involving a spectrum of hyperkinetic movement disorders alongside neuropsychiatric and multisystemic manifestations. Furthermore, during infancy and early childhood, transient motor phenomena resembling chorea occurring due to the rapid nervous system development during this period can complicate the diagnosis. This review aims to provide an overview of the main genetic causes of pediatric chorea that may manifest during infancy and early childhood, focusing on peculiarities that can aid in differential diagnosis among different phenotypes and discussing possible treatment options.
... ADCY4 mediated the activation of intracellular Ca 2+ , which might influence carcinogenesis and adverse invasion of lung adenocarcinoma cells (27). Some studies have reported that ADCY5 plays a role in the genesis and development of neurobiological diseases, including dyskinesia, early onset autosomal dominant chorea, and dystonia (28,29). ...
Background
The adenylyl cyclase (ADCY) gene family encodes enzymes responsible for the synthesis of cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP), which comprises nine transmembrane isoforms (ADCYs 1–9). Although ADCYs correlate with intracellular signalling and tumorigenesis in different malignancies, their roles in bladder cancer remain unclear.
Methods
Utilizing the bladder urothelial carcinoma (BLCA) dataset from The Cancer Genome Atlas (TCGA), we employed the R package ‘limma’ to identify differential genes. Subsequent correlation analysis with corresponding clinical data was conducted. Prognostic significance of ADCY family genes was assessed through survival analysis. Univariate and multivariate Cox regression determined ADCY2 as a potential independent risk factor for BLCA. Validation was performed using immunohistochemistry results from independent cohorts. Additionally, we delved into the mechanism of genetic variations, methylation modifications, and signalling pathways of ADCY family genes. Evaluation of their role in the immune microenvironment was achieved through R packages single-sample gene set enrichment analysis (ssGSEA), CIBERPORT, and ESTIMATE.
Results
Cases of bladder cancer were retrieved from TCGA, and the transcriptionally differentially expressed members of ADCY were identified (members 2, 4, and 5). Genomic alteration, epigenomic modification, clinicopathological characteristics and clinical survival were systematically investigated. A co-expression network was established based on the intersection of correlated genes, which was centred around ADCY2, ADCY4, and ADCY5. Enrichment analysis revealed that correlated genes were involved in epithelial-mesenchymal transition (EMT). The ADCY2 was selected as the most representative biomarker for prognosis in bladder cancer. Bladder tumour with higher ADCY2 expression had higher prognostic risk and worse survival outcomes. Moreover, ADCY2 was correlated with classic immune checkpoints, and a better responsiveness to immunotherapy was exhibited in high-expression subsets. To ameliorate universality of the conclusion, our study also included several real-world cohorts into the preliminary validation, using datasets from the Gene Expression Omnibus (GEO; GSE13507), tissue microarray (TMA) with 80 bladder cancer inclusion and clinical trial IMvigor210, which were associated with immunotherapy sensitivity, prognosis, and common biomarker presentation.
Conclusions
Our study reveals that ADCY family has prognostic value in patients with bladder cancer; the ADCY2 is a prominent prognostic biomarker. The bioinformatics analyses and validation provide direction for further functional and mechanistic studies on the screened members of ADCY family.
... Multiple SNPs have been identified in human ADCY5 and are linked to various disorders such as diabetes 25 , obesity 26 and central nervous system disorders 27 (Fig. 4a). Many of the SNPs are in regions known to be involved in modulation of AC activity, including six in the coiled-coil domain (Fig. 4b), six in C 1b (Fig. 4c) and ten in the catalytic domains (Fig. 4d). ...
The nine different membrane-anchored adenylyl cyclase isoforms (AC1–9) in mammals are stimulated by the heterotrimeric G protein, Gαs, but their response to Gβγ regulation is isoform specific. In the present study, we report cryo-electron microscope structures of ligand-free AC5 in complex with Gβγ and a dimeric form of AC5 that could be involved in its regulation. Gβγ binds to a coiled-coil domain that links the AC transmembrane region to its catalytic core as well as to a region (C1b) that is known to be a hub for isoform-specific regulation. We confirmed the Gβγ interaction with both purified proteins and cell-based assays. Gain-of-function mutations in AC5 associated with human familial dyskinesia are located at the interface of AC5 with Gβγ and show reduced conditional activation by Gβγ, emphasizing the importance of the observed interaction for motor function in humans. We propose a molecular mechanism wherein Gβγ either prevents dimerization of AC5 or allosterically modulates the coiled-coil domain, and hence the catalytic core. As our mechanistic understanding of how individual AC isoforms are uniquely regulated is limited, studies such as this may provide new avenues for isoform-specific drug development.
... The ADCY5 protein has two catalytic cyclase domains (C1 and C2) responsible for ATP binding and hydrolysis [8]. Most mutations occur in these two domains with an implication of enzyme-substrate binding (increased affinity to stimulatory factors) or inter-domain, possibly ligand-independent, interactions affecting the formation of the catalytic site [9]. Mutations affecting function of C1a and C2a catalytic domains are predicted to result in more severe presentations. ...
... The disorder is genetically heterogeneous, with most cases presenting as gain-of-function mutants. Loss-of-function and ADCY5 haploinsufficiency also occur [9,16]. The most common mutation hotspot is located on residue arginine 418 of the cytoplasmic domain C1 [9]. ...
... Loss-of-function and ADCY5 haploinsufficiency also occur [9,16]. The most common mutation hotspot is located on residue arginine 418 of the cytoplasmic domain C1 [9]. ...
Introduction:
ADCY5-related dyskinesia is a rare neurological disease caused by mutations in the gene encoding the adenylyl cyclase 5 (ADCY5) isoform, a protein that plays an important role in intracellular transmission. Variants in ADCY5 are associated with a spectrum of neurological disease encompassing dyskinesia, chorea, and dystonia. State of the-art. ADCY5 mutations result in clinically heterogeneous manifestations which comprise a range of core and less to highly variable symptoms. Due to the heterogeneous nature and difficulty in diagnosis of the disorder, available treatments are highly limited.
Clinical implications:
ADCY5-related dyskinesia was reported in 52 individuals in the literature over a five-year period (January 2017 to January 2022). We have listed all the symptoms and their frequency. The most common symptom reported in these patients was dystonia. Over 50% of patients developed dyskinesia and chorea. We report two cases of familial occurrence of symptomatic ADCY5-related dyskinesia. A 45-year-old patient presented with involuntary movements which had been occurring since childhood. The proband's neurological examination revealed dysarthria, involuntary myoclonic twitches, and choreic movements. The patient's 9-year-old son had developed involuntary movements, mainly chorea and dystonia.
Future directions:
This paper aims to summarise the recent literature on ADCY5-related neurological disorders and to present a new case of a Polish family with ADCY5 mutation. Genetic diagnostics are important in the context of possible future targeted treatments.
... ADCY5 is highly expressed in the brain and myocardium (64). Mutations in ADCY5 have mainly been linked to various complex movement disorders often associated with neurodevelopmental phenotypes (65). However, the role of ADCY5 in the TME was not reported. ...
Background: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis and is highly metastatic. Our prior studies have demonstrated the critical role of axon guidance pathway genes in PDAC and the connection between neuronal development and the tumor microenvironment. A recent study newly identified 20 neuronal development genes [disks large homolog 2 (DLG2), neuron-glial-related cell adhesion molecule (NRCAM), neurexin3 (NRXN3), mitogen-activated protein kinase 10 (MAPK10), platelet-derived growth factor D (PDGFD), protein kinase C epsilon (PRKCE), potassium calcium-activated channel subfamily M alpha 1 (KCNMA1), polycystic kidney and hepatic disease 1 (PKHD1), neural cell adhesion molecule 1 (NCAM1), neuregulin-1 (NRG1), zinc finger protein 667 (ZNF667), cystic fibrosis transmembrane conductance regulator (CFTR), acyl-CoA medium-chain synthetase-3 (ACSM3), complement 6 (C6), protein tyrosine phosphatase receptor type M (PTPRM), hypoxia-inducible factor 1 alpha (HIF1A), adenylyl cyclase 5 (ADCY5), adherens junctions-associated protein 1 (AJAP1), neurobeachin (NBEA), sodium voltage-gated channel alpha subunit 9 (SCN9A)] that are associated with perineural invasion and poor prognosis of PDAC. The relationship between genetic alterations in these 20 genes and tumor immune microenvironment (TME) has not previously been investigated. Methods: We hence applied the sequential multiplex immunohistochemistry results of biopsy specimens from 63 PDAC patients to investigate this relationship. Results: We found that, except for PTPRM and NBEA, genetic alterations involving these 20 genes are associated with significant changes in the densities of major immune cell subtypes. Except for AJAP1, the copy number loss involving this panel of neuronal development genes is significantly associated with changes in immune cell infiltrates. In contrast, the copy number gain in fewer genes, including NRXN3, ZNF667, ACSM3, C6, ADCY5, SCN9A, and PRKCE, is significantly associated with changes in immune cell infiltrates. Conclusions: Our study suggested that neuronal development genes play a role in modulating TME in a pancreatic cancer setting.
... The ADCY5 gene encodes adenylate cyclase type 5 (AC5), an enzyme involved in the conversion of adenosine triphosphate (ATP) to cyclic adenosine-3 ′ ,5 ′ -monophosphate (cAMP). cAMP is a secondary messenger involved in many cellular signaling pathways (5). AC5 is primarily expressed in the striatum, so heterozygous pathogenic variants in the ADCY5 gene affect the movement of regulatory systems (6). ...
... receptors potentializes the effects of D2 receptors, reinforces the dopamine inhibitory pathway, and decreases ADCY5 activity and the occurrence of dyskinesia (5). A retrospective study on the efficacy of caffeine in the management of ADCY5-related dyskinesia reported that 87% of patients respond to caffeine (21). ...
In this case study, we report the case of a 13-year-old girl with citrullinemia type 1 (MIM #215700), an autosomal recessive inherited disorder of the urea cycle, which was confirmed by the identification of a homozygous pathogenic variant in the argininosuccinate synthetase 1 (ASS1) gene. However, the patient presented abnormal hyperkinetic movements with global developmental delay and clinical signs that were not fully consistent with those of citrullinemia type 1 or with those of her siblings with isolated citrullinemia type 1. Exome sequencing showed the presence of a de novo heterozygous pathogenic variant in the adenylate cyclase type 5 (ADCY5) gene. The variant confirmed the overlap with the so-called ADCY5-related dyskinesia with orofacial involvement, which is autosomal dominant (MIM #606703), a disorder disrupting the enzymatic conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). In addition to the citrullinemia-related low-protein diet and arginine supplementation, the identification of this second disease led to the introduction of a treatment with caffeine, which considerably improved the dyskinesia neurological picture. In conclusion, this case highlights the importance of clinical-biological confrontation for the interpretation of genetic variants, as one hereditary metabolic disease may hide another with therapeutic consequences.
Summary
This article reports the misleading superposition of two inherited metabolic diseases, showing the importance of clinical-biological confrontation in the interpretation of genetic variants.
... As several of these conditions may be amenable to different specific therapeutic purposes, such as ketogenic diet, vitamin or cofactor supplementation, and diet restrictions, early diagnosis is essential to provide targeted therapies with better outcomes 1 . ADCY5-related dyskinesia is a rare autosomal dominant neurogenetic disease, which can present with childhood-onset complex association of hyperkinetic movement disorders [2][3][4] . Several groups have recommended the use of caffeine as a potential treatment option 3,5 . ...
... ADCY5-related dyskinesia is a rare autosomal dominant neurogenetic disease, which can present with childhood-onset complex association of hyperkinetic movement disorders [2][3][4] . Several groups have recommended the use of caffeine as a potential treatment option 3,5 . We present herein and discuss the case of a middle-aged man with long-standing clinical course of ADCY5-related dyskinesia and marked clinical improvement after caffeine association with benzodiazepine. ...
Case Report. A 40-year-old Brazilian man presented with long-standing loss of balance, dystonia, and choreoathetosis, with episodic paroxysmal worsening. Neuroimaging and cerebrospinal fluid analysis were both unremarkable. Quantitative urine organic acid analysis, plasma acylcarnitine quantitative profile, and quantitative analysis of plasma amino acids by high performance liquid chromatography were all within normal interval values. Multigene next-generation sequencing panel identified the heterozygous pathogenic variant c.1252C>T (p.Arg418Trp) in the ADCY5 gene, defining a diagnosis of ADCY5-related dyskinesia. Oral caffeine was associated to clonazepam and provided marked improvement of motor symptoms. Conclusion. This report adds evidence to the safety and efficacy of caffeine in the treatment of genetically confirmed cases of ADCY5-related dyskinesia in the context of gain-of-function variants.
... Adenylyl cyclase is responsible for the conversion of adenosine triphosphate (ATP) to cyclic adenosine-3 ′ ,5 ′ -monophosphate (cAMP) and is involved in dopaminergic signaling. Dysfunction of the cAMP pathway can contribute to postsynaptic movement disorders such as dystonia, chorea, and parkinsonism (Abela and Kurian, 2018;Ferrini et al., 2021). A novel variant of ADCY5 evaluated to be potentially pathogenic was identified in our cohort, and the burden of rare variants in ADCY5 was increased in sEOPD, which suggested the involvement of ADCY5 in the pathogenesis of PD, whereas research of the underlying mechanisms is further needed. ...
Objective:
Parkinson's disease (PD) and dystonia are two closely related movement disorders with overlaps in clinical phenotype. Variants in several dystonia-related genes were demonstrated to be associated with PD; however, genetic evidence for the involvement of dystonia-related genes in PD has not been fully studied. Here, we comprehensively investigated the association between rare variants in dystonia-related genes and PD in a large Chinese cohort.
Methods:
We comprehensively analyzed the rare variants of 47 known dystonia-related genes by mining the whole-exome sequencing (WES) and whole-genome sequencing (WGS) data from 3,959 PD patients and 2,931 healthy controls. We initially identified potentially pathogenic variants of dystonia-related genes in patients with PD based on different inheritance models. Sequence kernel association tests were conducted in the next step to detect the association between the burden of rare variants and the risk for PD.
Results:
We found that five patients with PD carried potentially pathogenic biallelic variants in recessive dystonia-related genes including COL6A3 and TH. Additionally, we identified 180 deleterious variants in dominant dystonia-related genes based on computational pathogenicity predictions and four of which were considered as potentially pathogenic variants (p.W591X and p.G820S in ANO3, p.R678H in ADCY5, and p.R458Q in SLC2A1). A gene-based burden analysis revealed the increased burden of variant subgroups of TH, SQSTM1, THAP1, and ADCY5 in sporadic early-onset PD, whereas COL6A3 was associated with sporadic late-onset PD. However, none of them reached statistical significance after the Bonferroni correction.
Conclusion:
Our findings indicated that rare variants in several dystonia-related genes are suggestively associated with PD, and taken together, the role of COL6A3 and TH genes in PD is highlighted.
