RESUMEN
X-linked dystonia-parkinsonism (XDP) is a severe neurodegenerative disorder that manifests as adult-onset dystonia combined with parkinsonism. A SINE-VNTR-Alu (SVA) retrotransposon inserted in an intron of the TAF1 gene reduces its expression and alters splicing in XDP patient-derived cells. As a consequence, increased levels of the TAF1 intron retention transcript TAF1-32i can be found in XDP cells as compared to healthy controls. Here, we investigate the sequence of the deep intronic region included in this transcript and show that it is also present in cells from healthy individuals, albeit in lower amounts than in XDP cells, and that it undergoes degradation by nonsense-mediated mRNA decay. Furthermore, we investigate epigenetic marks (e.g., DNA methylation and histone modifications) present in this intronic region and the spanning sequence. Finally, we show that the SVA evinces regulatory potential, as demonstrated by its ability to repress the TAF1 promoter in vitro. Our results enable a better understanding of the disease mechanisms underlying XDP and transcriptional alterations caused by SVA retrotransposons.
Asunto(s)
Trastornos Distónicos/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Trastornos Parkinsonianos/genética , Retroelementos/genética , Transcripción Genética/genética , Adolescente , Adulto , Metilación de ADN/genética , Femenino , Histona Acetiltransferasas/genética , Humanos , Intrones/genética , Masculino , Persona de Mediana Edad , Regiones Promotoras Genéticas/genética , Elementos de Nucleótido Esparcido Corto/genética , Factores Asociados con la Proteína de Unión a TATA/genética , Factor de Transcripción TFIID/genética , Adulto JovenRESUMEN
A plethora of heterogeneous movement disorders is grouped under the umbrella term dystonia. The clinical presentation ranges from isolated dystonia to multi-systemic disorders where dystonia is only a co-occurring sign. In the past, definitions, nomenclature, and classifications have been repeatedly refined, adapted, and extended to reflect novel findings and increasing knowledge about the clinical, etiologic, and scientific background of dystonia. Currently, dystonia is suggested to be classified according to two axes. The first axis offers precise categories for the clinical presentation grouped into age at onset, body distribution, temporal pattern and associated features. The second, etiologic, axis discriminates pathological findings, as well as inheritance patterns, mode of acquisition, or unknown causality. Furthermore, the recent recommendations regarding terminology and nomenclature of inherited forms of dystonia and related syndromes are illustrated in this article. Harmonized, specific, and internationally widely used classifications provide the basis for future systematic dystonia research, as well as for more personalized patient counseling and treatment approaches.
Asunto(s)
Distonía , Trastornos Distónicos , Trastornos del Movimiento , Edad de Inicio , Causalidad , Distonía/diagnóstico , Distonía/etiología , Trastornos Distónicos/diagnóstico , Trastornos Distónicos/etiología , HumanosRESUMEN
Myoclonus-dystonia (DYT-SGCE, formerly DYT11) is characterized by alcohol-sensitive, myoclonic-like appearance of fast dystonic movements. It is caused by mutations in the SGCE gene encoding ε-sarcoglycan leading to a dysfunction of this transmembrane protein, alterations in the cerebello-thalamic pathway and impaired striatal plasticity. To elucidate underlying pathogenic mechanisms, we investigated induced pluripotent stem cell (iPSC)-derived striatal medium spiny neurons (MSNs) from two myoclonus-dystonia patients carrying a heterozygous mutation in the SGCE gene (c.298T>G and c.304C>T with protein changes W100G and R102X) in comparison to two matched healthy control lines. Calcium imaging showed significantly elevated basal intracellular Ca2+ content and lower frequency of spontaneous Ca2+ signals in SGCE MSNs. Blocking of voltage-gated Ca2+ channels by verapamil was less efficient in suppressing KCl-induced Ca2+ peaks of SGCE MSNs. Ca2+ amplitudes upon glycine and acetylcholine applications were increased in SGCE MSNs, but not after GABA or glutamate applications. Expression of voltage-gated Ca2+ channels and most ionotropic receptor subunits was not altered. SGCE MSNs showed significantly reduced GABAergic synaptic density. Whole-cell patch-clamp recordings displayed elevated amplitudes of miniature postsynaptic currents and action potentials in SGCE MSNs. Our data contribute to a better understanding of the pathophysiology and the development of novel therapeutic strategies for myoclonus-dystonia.
Asunto(s)
Cuerpo Estriado/patología , Espinas Dendríticas/patología , Trastornos Distónicos/patología , Acetilcolina/farmacología , Potenciales de Acción , Adulto , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo L/metabolismo , Señalización del Calcio , Diferenciación Celular/fisiología , Células Cultivadas , Espinas Dendríticas/efectos de los fármacos , Espinas Dendríticas/metabolismo , Femenino , Expresión Génica , Glicina/farmacología , Humanos , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/fisiología , Masculino , Mecamilamina/farmacología , Persona de Mediana Edad , Técnicas de Placa-ClampRESUMEN
OBJECTIVE: X-linked dystonia parkinsonism (XDP) is a neurodegenerative movement disorder caused by a single mutation: SINE-VNTR-Alu (SVA) retrotransposon insertion in TAF1. Recently, a (CCCTCT)n repeat within the SVA insertion has been reported as an age-at-onset (AAO) modifier in XDP. Here we investigate the role of this hexanucleotide repeat in modifying expressivity of XDP. METHODS: We genotyped the hexanucleotide repeat in 355 XDP patients and correlated the repeat number (RN) with AAO (n = 295), initial clinical manifestation (n = 294), site of dystonia onset (n = 238), disease severity (n = 28), and cognitive function (n = 15). Furthermore, we investigated i) repeat instability by segregation analysis and Southern blotting using postmortem brain samples from two affected individuals and ii) relative TAF1 expression in blood RNA from 31 XDP patients. RESULTS: RN showed significant inverse correlations with AAO and with TAF1 expression and a positive correlation with disease severity and cognitive dysfunction. Importantly, AAO (and not RN) was directly associated with whether dystonia or parkinsonism will manifest at onset. RN was lower in patients affected by mouth/tongue dystonia compared with blepharospasm. RN was unstable across germline transmissions with an overall tendency to increase in length and exhibited somatic mosaicism in brain. INTERPRETATION: The hexanucleotide repeat within the SVA insertion acts as a genetic modifier of disease expressivity in XDP. RN-dependent TAF1 repression and subsequent differences in TAF1 mRNA levels in patients may be potentiated in the brain through somatic variability leading to the neurological phenotype. ANN NEUROL 2019;85:812-822.
Asunto(s)
Expansión de las Repeticiones de ADN/genética , Trastornos Distónicos/diagnóstico , Trastornos Distónicos/genética , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Histona Acetiltransferasas/genética , Secuencias Repetitivas de Ácidos Nucleicos/genética , Factores Asociados con la Proteína de Unión a TATA/genética , Factor de Transcripción TFIID/genética , Adulto , Trastornos Distónicos/metabolismo , Femenino , Expresión Génica , Enfermedades Genéticas Ligadas al Cromosoma X/metabolismo , Histona Acetiltransferasas/biosíntesis , Humanos , Masculino , Factores Asociados con la Proteína de Unión a TATA/biosíntesis , Factor de Transcripción TFIID/biosíntesis , Adulto JovenRESUMEN
BACKGROUND: X-linked dystonia-parkinsonism is a neurodegenerative movement disorder. The underlying molecular basis has still not been completely elucidated, but likely involves dysregulation of TAF1 expression. In X-linked dystonia-parkinsonism, 3 disease-specific single-nucleotide changes (DSCs) introduce (DSC12) or abolish (DSC2 and DSC3) CpG dinucleotides and consequently sites of putative DNA methylation. Because transcriptional regulation tightly correlates with specific epigenetic marks, we investigated the role of DNA methylation in the pathogenesis of X-linked dystonia-parkinsonism. METHODS: DNA methylation at DSC12, DSC3, and DSC2 was quantified by bisulfite pyrosequencing in DNA from peripheral blood leukocytes, fibroblasts, induced pluripotent stem cell-derived cortical neurons and brain tissue from X-linked dystonia-parkinsonism patients and age- and sex-matched healthy Filipino controls in a prospective study. RESULTS: Compared with controls, X-linked dystonia-parkinsonism patients showed striking differences in DNA methylation at the 3 investigated CpG sites. Using methylation-sensitive luciferase reporter gene assays and immunoprecipitation, we demonstrated (1) that lack of DNA methylation because of DSC2 and DSC3 affects gene promoter activity and (2) that methylation at all 3 investigated CpG sites alters DNA-protein interaction. Interestingly, DSC3 decreased promoter activity per se compared with wild type, and promoter activity further decreased when methylation was present. Moreover, we identified specific binding of proteins to the investigated DSCs that are associated with splicing and RNA and DNA binding. CONCLUSIONS: We identified altered DNA methylation in X-linked dystonia-parkinsonism patients as a possible additional mechanism modulating TAF1 expression and putative novel targets for future therapies using DNA methylation-modifying agents. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Asunto(s)
Factores Asociados con la Proteína de Unión a TATA , Factor de Transcripción TFIID , Metilación de ADN/genética , Trastornos Distónicos , Enfermedades Genéticas Ligadas al Cromosoma X , Histona Acetiltransferasas/metabolismo , Humanos , Estudios Prospectivos , Factores Asociados con la Proteína de Unión a TATA/genética , Factores Asociados con la Proteína de Unión a TATA/metabolismo , Factor de Transcripción TFIID/genética , Factor de Transcripción TFIID/metabolismoRESUMEN
DYT-TOR1A is the most common inherited dystonia caused by a three nucleotide (GAG) deletion (dE) in the TOR1A gene. Death early after birth and cortical anomalies of the full knockout in rodents underscore its developmental importance. We therefore explored the timed effects of TOR1A-wt and TOR1A-dE during differentiation in a human neural in vitro model. We used lentiviral tet-ON expression of TOR1A-wt and -dE in induced neural stem cells derived from healthy donors. Overexpression was induced during proliferation of neural precursors, during differentiation and after differentiation into mature neurons. Overexpression of both wildtype and mutated protein had no effect on the viability and cell number of neural precursors as well as mature neurons when initiated before or after differentiation. However, if induced during differentiation, overexpression of TOR1A-wt and -dE led to a pronounced reduction of mature neurons in a dose dependent manner. Our data underscores the importance of physiological expression levels of TOR1A as crucial for proper neuronal differentiation. We did not find evidence for a specific impact of the mutated TOR1A on neuronal maturation.
Asunto(s)
Chaperonas Moleculares/biosíntesis , Células-Madre Neurales/metabolismo , Neuronas/metabolismo , Diferenciación Celular/fisiología , Distonía/genética , Distonía/metabolismo , Distonía/patología , Células HEK293 , Humanos , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Mutación , Células-Madre Neurales/patología , Neuronas/patologíaRESUMEN
BACKGROUND: The most likely genetic cause of X-linked dystonia-parkinsonism, a neurodegenerative movement disorder endemic to the Philippines, is a 2672-bp-long retrotransposon insertion in intron 32 of the TAF1 gene. The objectives of this study were to investigate whether (1) TAF1 expression is altered in induced pluripotent stem cells and differentiated neuronal models and (2) excision of the retrotransposon insertion restores normal TAF1 expression. METHODS: Expression of TAF1 and its neuronal isoform were determined in induced pluripotent stem cells and in induced pluripotent stem cell-derived cortical neurons and spiny projection neurons using quantitative PCR. Genome editing-based excision of the retrotransposon insertion was performed on induced pluripotent stem cells from 3 X-linked dystonia-parkinsonism patients. Edited and unedited induced pluripotent stem cells from X-linked dystonia-parkinsonism patients and controls were differentiated into cortical neurons and spiny projection neurons, and TAF1 expression was compared across groups. RESULTS: TAF1 was reduced in patient-derived induced pluripotent stem cells (P < 0.05) and spiny projection neurons (P < 0.01). After genome editing, we observed higher TAF1 expression in edited compared with unedited induced pluripotent stem cells (P < 0.0001). In edited spiny projection neurons, TAF1 expression was also increased, but did not reach statistical significance. No expression differences were observed in cortical neurons. CONCLUSIONS: (1) TAF1 reduction in X-linked dystonia-parkinsonism is likely due to the retrotransposon insertion and is recapitulated in induced pluripotent stem cells and differentiated spiny projection neurons. (2) TAF1 reduction is a tractable molecular phenotype of X-linked dystonia-parkinsonism that can be driven by excision of the retrotransposon insertion. (3) Successful rescue of the molecular phenotype in an endogenous, genome-edited model serves as a proof of principle that may successfully be transferred to other inherited neurodegenerative diseases. © 2018 International Parkinson and Movement Disorder Society.
Asunto(s)
Trastornos Distónicos/genética , Trastornos Distónicos/metabolismo , Edición Génica/métodos , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/metabolismo , Histona Acetiltransferasas/metabolismo , Células Madre Pluripotentes Inducidas/fisiología , Factores Asociados con la Proteína de Unión a TATA/metabolismo , Factor de Transcripción TFIID/metabolismo , Adulto , Células Cultivadas , Corteza Cerebral/citología , Femenino , Factor 3 de Diferenciación de Crecimiento/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Proteína Homeótica Nanog/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , ARN Mensajero/metabolismo , Factores de Transcripción SOXB1/genética , Factores de Transcripción SOXB1/metabolismo , Transfección , Tubulina (Proteína)/metabolismoRESUMEN
Mutations in the adenylate cyclase 5 (ADCY5) gene recently have been identified as the cause of a childhood-onset disorder characterized by persistent or paroxysmal choreic, myoclonic, and/or dystonic movements. The 2 novel mutations we identified expand the clinical spectrum of ADCY5 mutations to include alternating hemiplegia of childhood.
Asunto(s)
Adenilil Ciclasas/genética , Hemiplejía/genética , Adolescente , Niño , Humanos , Masculino , MutaciónRESUMEN
The molecular dysfunction in X-linked dystonia-parkinsonism is not completely understood. Thus far, only noncoding alterations have been found in genetic analyses, located in or nearby the TATA-box binding protein-associated factor 1 (TAF1) gene. Given that this gene is ubiquitously expressed and is a critical component of the cellular transcription machinery, we sought to study differential gene expression in peripheral models by performing microarray-based expression profiling in blood and fibroblasts, and comparing gene expression in affected individuals vs. ethnically matched controls. Validation was performed via quantitative polymerase chain reaction in discovery and independent replication sets. We observed consistent downregulation of common TAF1 transcripts in samples from affected individuals in gene-level and high-throughput experiments. This signal was accompanied by a downstream effect in the microarray, reflected by the dysregulation of 307 genes in the disease group. Gene Ontology and network analyses revealed enrichment of genes involved in RNA polymerase II-dependent transcription, a pathway relevant to TAF1 function. Thus, the results converge on TAF1 dysfunction in peripheral models of X-linked dystonia-parkinsonism, and provide evidence of altered expression of a canonical gene in this disease. Furthermore, our study illustrates a link between the previously described genetic alterations and TAF1 dysfunction at the transcriptome level.
Asunto(s)
Trastornos Distónicos/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Histona Acetiltransferasas/genética , Factores Asociados con la Proteína de Unión a TATA/genética , Factor de Transcripción TFIID/genética , Redes Reguladoras de Genes , Humanos , Masculino , Activación Transcripcional , TranscriptomaRESUMEN
BACKGROUND: Linkage analyses of families with primary familial brain calcification (formerly idiopathic basal ganglia calcification [IBGC]) identified 3 candidate loci (IBGC1-3). Recently, SLC20A2 mutations were found in the IBGC1 and IBGC3 families, merging these 2 loci. We here elucidate the genetic cause of primary familial brain calcification in the 'IBGC2' kindred. METHODS: We sequenced known primary familial brain calcification genes and quantified SLC20A2 and PDGFB. Moreover, CT scans of affected and unaffected family members were evaluated by 2 blinded neuroradiologists for distribution of brain calcification. RESULTS: A heterozygous multiexonic SLC20A2 deletion was detected in several affected family members. A reevaluation of neuroimaging data revealed a subset of mutation-negative individuals with only mild and/or unilateral calcification. CONCLUSIONS: The identified SLC20A2 mutation resolves the genetic cause of primary familial brain calcification in the 'IBGC2' kindred, collapsing 'IBGC2' into IBGC1. We suggest an algorithm for predicting the chances of finding genetic mutations that has to be validated in further studies. Our study enhances criteria for the evaluation of neuroimaging data, contributing further to the much needed harmonization of diagnostic and research data collection in primary familial brain calcification. © 2016 International Parkinson and Movement Disorder Society.
Asunto(s)
Enfermedades de los Ganglios Basales/diagnóstico por imagen , Enfermedades de los Ganglios Basales/genética , Calcinosis/diagnóstico por imagen , Calcinosis/genética , Enfermedades Neurodegenerativas/diagnóstico por imagen , Enfermedades Neurodegenerativas/genética , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo III/genética , Humanos , Linaje , Método Simple CiegoRESUMEN
OBJECTIVE: Our study investigated the presence of regional differences in hexanucleotide repeat number in postmortem brain tissues of 2 patients with X-linked dystonia-parkinsonism (XDP), a combined dystonia-parkinsonism syndrome modified by a (CCCTCT)n repeat within the causal SINE-VNTR-Alu retrotransposon insertion in the TAF1 gene. METHODS: Genomic DNA was extracted from blood and postmortem brain samples, including the basal ganglia and cortex from both patients and from the cerebellum, midbrain, and pituitary gland from 1 patient. Repeat sizing was performed using fragment analysis, small-pool PCR-based Southern blotting, and Oxford nanopore sequencing. RESULTS: The basal ganglia (p < 0.001) and cerebellum (p < 0.001) showed higher median repeat numbers and higher degrees of repeat instability compared with blood. CONCLUSIONS: Somatic repeat instability may predominate in brain regions selectively affected in XDP, thereby hinting at its potential role in disease manifestation and modification.
RESUMEN
X-linked dystonia-parkinsonism (XDP) is a monogenic neurodegenerative disorder of the basal ganglia, which presents as a combination of hyperkinetic movements and parkinsonian features. The underlying genetic mechanism involves the insertion of a SINE-VNTR-Alu retrotransposon within the TAF1 gene. Interestingly, alterations of TAF1 have been involved in multiple neurological diseases. In XDP, the SINE-VNTR-Alu insertion in TAF1 has been proposed to result in alternative splicing defects, including the decreased incorporation of a neuron-specific microexon annotated as 34'. This mechanism has become controversial as recent studies failed to provide support. In order to resolve this conundrum, we examined the alternative splicing patterns of TAF1 mRNAs in XDP and control brains. The impact of the disease-associated SINE-VNTR-Alu on alternative splicing of microexon 34' was further investigated in cellular assays. Subsequently, microexon 34' incorporation was explored by RT-PCR and Nanopore long-read sequencing of TAF1 mRNAs from XDP and control brains tissues. Using cell-based splicing assays, we demonstrate that presence of the disease-associated SINE-VNTR-Alu does not affect the inclusion of microexon 34'. In addition, we show that (1) microexon 34'-containing TAF1 mRNAs are detected at similar levels in XDP as in controls and that (2) the architecture of TAF1 transcripts is remarkably similar between XDP and controls brains. These results indicate that microexon 34' incorporation into TAF1 mRNA is not affected in XDP brains. Our findings shift the current paradigm of XDP by discounting alternative splicing of TAF1 microexon 34' as the molecular basis for this disease.
RESUMEN
X-linked dystonia-parkinsonism is a neurodegenerative disorder caused by a founder retrotransposon insertion, in which a polymorphic hexanucleotide repeat accounts for ~50% of age at onset variability. Employing a genome-wide association study to identify additional factors modifying age at onset, we establish that three independent loci are significantly associated with age at onset (p < 5 × 10-8). The lead single nucleotide polymorphisms collectively account for 25.6% of the remaining variance not explained by the hexanucleotide repeat and 13.0% of the overall variance in age at onset in X-linked dystonia-parkinsonism with the protective alleles delaying disease onset by seven years. These regions harbor or lie adjacent to MSH3 and PMS2, the genes that were recently implicated in modifying age at onset in Huntington's disease, likely through a common pathway influencing repeat instability. Our work indicates the existence of three modifiers of age at onset in X-linked dystonia-parkinsonism that likely affect the DNA mismatch repair pathway.
Asunto(s)
Trastornos Distónicos/genética , Genes Modificadores , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Sitios Genéticos , Penetrancia , Adulto , Edad de Inicio , Anciano , Alelos , Estudios de Casos y Controles , Reparación de la Incompatibilidad de ADN , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Factores Protectores , Adulto JovenRESUMEN
Despite a genetic component in the development of Parkinson's disease (PD), monozygotic twin pairs often display discordance for PD. Here, we describe the generation of six human induced pluripotent stem cell (iPSC) lines from dermal fibroblasts of three pairs of monozygotic twins discordant for PD. We used non-integrating Sendai virus and the iPSC lines were comprehensively characterized. These lines provide a valuable resource for studying molecular differences between the affected and unaffected monozygotic twin and their response to genetic and non-genetic factors that might be involved in the development of PD.
Asunto(s)
Técnicas de Cultivo de Célula/métodos , Células Madre Pluripotentes Inducidas/patología , Enfermedad de Parkinson/patología , Gemelos Monocigóticos , Anciano , Biomarcadores/metabolismo , Línea Celular , Regulación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los ResultadosRESUMEN
OBJECTIVE: A clinical feature in patients with ADCY5 gene mutations are perioral muscle twitches initially described as facial myokymia. METHODS: Five patients with ADCY5-associated disease with facial twitches and truncal jerks underwent electrophysiological investigations of the orbicularis oris and trapezius muscles to delineate neurophysiological characteristics of these phenomena. RESULTS: Electromyography (EMG) recordings showed a complex electrophysiological pattern with brief bursts of less than 100 ms and longer bursts with a duration of 100-300 ms up to several seconds in keeping with myoclonus and chorea, respectively, as key findings. None of the patients had EMG patterns of myokymia. CONCLUSIONS: In this series of five ADCY5 mutation carriers, perioral twitches and truncal jerks do not represent myokymia. In view of characteristic clinical signs and electrophysiological patterns with a combination of myoclonus and chorea it might be preferable to refer to these phenomena as myoclonus-chorea.
Asunto(s)
Adenilil Ciclasas/genética , Corea/fisiopatología , Mioclonía/fisiopatología , Miocimia/genética , Adulto , Corea/genética , Electromiografía/métodos , Músculos Faciales/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Mioclonía/diagnóstico , Mioclonía/genética , Miocimia/diagnósticoRESUMEN
In neuropathology research, induced pluripotent stem cell (iPSC)-derived neurons are considered a tool closely resembling the patient brain. Albeit in respect to epigenetics, this concept has been challenged. We generated iPSC-derived cortical neurons from myoclonus-dystonia patients with mutations (W100G and R102X) in the maternally imprinted ε-sarcoglycan (SGCE) gene and analysed properties such as imprinting, mRNA and protein expression. Comparison of the promoter during reprogramming and differentiation showed tissue-independent differential methylation. DNA sequencing with methylation-specific primers and cDNA analysis in patient neurons indicated selective expression of the mutated paternal SGCE allele. While fibroblasts only expressed the ubiquitous mRNA isoform, brain-specific SGCE mRNA and ε-sarcoglycan protein were detected in iPSC-derived control neurons. However, neuronal protein levels were reduced in both mutants. Our phenotypic characterization highlights the suitability of iPSC-derived cortical neurons with SGCE mutations for myoclonus-dystonia research and, in more general terms, prompts the use of iPSC-derived cellular models to study epigenetic mechanisms impacting on health and disease.