RESUMEN
Undiagnosed rare diseases (URDs) account for a significant portion of the overall rare disease burden, depending upon the country. Hence, URDs represent an unmet medical need. A specific challenge posed by the ensemble of the URD patient cohort is the heterogeneity of its composition; the group, indeed, includes very rare, still unidentified conditions as well as clinical variants of recognized rare diseases. Exact disease recognition requires new approaches that cut across national and institutional boundaries, may need the implementation of methods new to diagnostics, and embrace clinical care and research. To address these issues, the Undiagnosed Diseases Network International (UDNI) was established in 2014, with the major aims of providing diagnoses to patients, implementing additional diagnostic tools, and fostering research on novel diseases, their mechanisms, and their pathways. The UDNI involves centres with internationally recognized expertise, and its scientific resources and know-how aim to fill the knowledge gaps that impede diagnosis, in particularly for ultra-rare diseases. Consequently, the UDNI fosters the translation of research into medical practice, aided by active patient involvement. The goals of the UDNI are to work collaboratively and at an international scale to: 1) provide diagnoses for individuals who have conditions that have eluded diagnosis by clinical experts; 2) gain insights into the etiology and pathogenesis of novel diseases; 3) contribute to standards of diagnosing unsolved patients; and 4) share the results of UDNI research in a timely manner and as broadly as possible.
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Salud Global , Servicios de Información/organización & administración , Cooperación Internacional , Enfermedades Raras/diagnóstico , Enfermedades no Diagnosticadas , Investigación Biomédica , Humanos , Enfermedades Raras/etiología , Factores de TiempoRESUMEN
Olfactory dysfunction is observed in several neurological disorders, including Huntington disease (HD), and correlates with global cognitive performance, depression and degeneration of olfactory regions in the brain. Despite clear evidence demonstrating olfactory dysfunction in HD patients, only limited details are available in murine models and the underlying mechanisms are unknown. In order to determine if alterations in the olfactory bulb (OB) are observed in HD we assessed OB weight or area from 3 to 12â¯months of age in the BACHD transgenic lines (TG5 and TG9). A significant decrease in the OB was observed at 6 and 12â¯months of age compared to WT. We also detected increased mRNA and protein expression of mutant huntingtin (mHTT) in the OB of TG5 compared to TG9 at specific ages. Despite the higher expression of mHTT in the TG5 OBs, there was increased nuclear accumulation of mHTT in the OB of TG9 compared to WT and TG5 rats. As we observed atrophy of the OB in the BACHD rats we assessed for caspase activation, a known mechanism underlying the cell death observed in HD. We characterized caspase-3, -6, -8 andâ¯-â¯9 mRNA and protein expression levels in the OB of the BACHD transgenic lines at 3, 6 and 12â¯months of age. Alterations in caspase mRNA and protein expression were detected in the TG5 and TG9 lines. However, the changes observed in the mRNA and protein levels are in some cases discordant, suggesting that the caspase protein modifications detected may be more attributable to post-translational modifications. The caspase activation studies support that cell death may be increased in the rodent HD OB and further our understanding of the olfactory dysfunction and the role of caspases in the pathogenesis of HD.
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Caspasas/metabolismo , Enfermedad de Huntington/complicaciones , Trastornos del Olfato/etiología , Bulbo Olfatorio/enzimología , Bulbo Olfatorio/patología , Animales , Atrofia/etiología , Atrofia/patología , Modelos Animales de Enfermedad , Activación Enzimática/fisiología , Humanos , Proteína Huntingtina/genética , Enfermedad de Huntington/enzimología , Enfermedad de Huntington/patología , Trastornos del Olfato/enzimología , Trastornos del Olfato/patología , Ratas , Ratas TransgénicasRESUMEN
SHORT syndrome (OMIM 269880) is a rare autosomal-dominant disorder characterized by short stature, hyperextensibility of joints, hernias, ocular depression, ophthalmic anomalies (Rieger anomaly, posterior embryotoxon, glaucoma), teething delay, partial lipodystrophy, insulin resistance and facial dysmorphic signs. Heterozygous mutations in PIK3R1 were recently identified in 14 families with SHORT syndrome. Eight of these families had a recurrent missense mutation (c.1945C>T; p.Arg649Trp). We report on two unrelated patients with typical clinical features of SHORT syndrome and additional problems such as pulmonary stenosis and ectopic kidney. Analysis of PIK3R1 revealed the mutation c.1945C>T; p.Arg649Trp de novo in both patients. These two patients not only provide additional evidence that PIK3R1 mutations cause SHORT syndrome, but also broaden the clinical spectrum of this syndrome and further confirm that the amino acid exchange c.1945C>T; p.Arg649Trp is a hotspot mutation in this gene.
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Predisposición Genética a la Enfermedad/genética , Trastornos del Crecimiento/genética , Trastornos del Crecimiento/patología , Hipercalcemia/genética , Hipercalcemia/patología , Enfermedades Metabólicas/genética , Enfermedades Metabólicas/patología , Nefrocalcinosis/genética , Nefrocalcinosis/patología , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasa Clase Ia , Cartilla de ADN/genética , Femenino , Heterocigoto , Humanos , Masculino , Mutación Missense/genética , Reacción en Cadena de la Polimerasa , Análisis de Secuencia de ADNRESUMEN
Intensive scientific research devoted in the recent years to understand the molecular mechanisms or neurodegeneration in spinocerebellar ataxias (SCAs) are identifying new pathways and targets providing new insights and a better understanding of the molecular pathogenesis in these diseases. In this consensus manuscript, the authors discuss their current views on the identified molecular processes causing or modulating the neurodegenerative phenotype in spinocerebellar ataxias with the common opinion of translating the new knowledge acquired into candidate targets for therapy. The following topics are discussed: transcription dysregulation, protein aggregation, autophagy, ion channels, the role of mitochondria, RNA toxicity, modulators of neurodegeneration and current therapeutic approaches. Overall point of consensus includes the common vision of neurodegeneration in SCAs as a multifactorial, progressive and reversible process, at least in early stages. Specific points of consensus include the role of the dysregulation of protein folding, transcription, bioenergetics, calcium handling and eventual cell death with apoptotic features of neurons during SCA disease progression. Unresolved questions include how the dysregulation of these pathways triggers the onset of symptoms and mediates disease progression since this understanding may allow effective treatments of SCAs within the window of reversibility to prevent early neuronal damage. Common opinions also include the need for clinical detection of early neuronal dysfunction, for more basic research to decipher the early neurodegenerative process in SCAs in order to give rise to new concepts for treatment strategies and for the translation of the results to preclinical studies and, thereafter, in clinical practice.
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Degeneración Nerviosa/fisiopatología , Degeneración Nerviosa/terapia , Ataxias Espinocerebelosas/fisiopatología , Ataxias Espinocerebelosas/terapia , Animales , Autofagia , Humanos , Canales Iónicos/metabolismo , Mitocondrias/fisiología , Degeneración Nerviosa/genética , Degeneración Nerviosa/patología , ARN/metabolismo , Ataxias Espinocerebelosas/genética , Ataxias Espinocerebelosas/patología , Transcripción GenéticaRESUMEN
BACKGROUND AND OBJECTIVES: The ataxias are a challenging group of neurological diseases due the aetiological heterogeneity and the complexity of the genetic subtypes. This guideline focuses on the heredodegenerative ataxias. The aim is to provide a peer-reviewed evidence-based guideline for clinical neurologists and other specialist physicians responsible for the care of patients with ataxia. METHODS: This guideline is based on systematic evaluations of the relevant literature and on three consensus meetings of the task force. DIAGNOSIS: If acquired causes are ruled out, and if the disease course is rather slowly progressive, a (heredo)degenerative disease is likely. A positive family history gives much guidance. In the case of a dominant family history, first line genetic screening is recommended for spinocerebellar ataxia (SCA) 1, 2, 3, 6, 7 and 17 (level B), and in Asian patients also for dentatorubral-pallidoluysian atrophy (DRPLA). In the case of recessive disease, a stepwise diagnostic work-up is recommended, including both biochemical markers and targeted genetic testing, particularly aimed at Friedreich's ataxia, ataxia telangiectasia, ataxia due to vitamin E deficiency, polymerase gamma gene (POLG gene, various mutations), autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) and ataxia with oculomotor apraxia (AOA) types 1 and 2. If family history is negative, we still advise to screen for the more common dominant and recessive ataxias. In addition, if onset is below 45 years we recommend the full work-up for recessive ataxias; if onset is above 45 years we recommend to screen for fragile X mental retardation 1 FMR1 premutations (good practice points). In sporadic cases with an onset after 30 years, a diagnosis of multiple system atrophy should be considered (good practice point). In particular the genetic work-up will change over the upcoming years due to the diagnostic utility of new techniques such as gene panel diagnostics based on next generation sequencing for routine work-up, or even whole exome and genome sequencing for selected cases. TREATMENT: Some of the rare recessive ataxias are treatable, but for most of the heredodegenerative ataxias treatment is purely symptomatic. Idebenone is not effective in Friedreich's ataxia (level A). Riluzole (level B) and amantadine (level C) might provide symptomatic relief, irrespective of exact etiology. Also, varenicline for SCA3 patients (level B) can be considered. There is level Class II evidence to recommend physiotherapy, and Class III data to support occupational therapy.
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Ataxia/diagnóstico , Ataxia/terapia , Consenso , Guías como Asunto/normas , Ataxia/genética , Enfermedad Crónica , Bases de Datos Factuales/estadística & datos numéricos , HumanosRESUMEN
To identify expressed sequences within candidate regions for the Huntington's disease (HD) gene in 4p16.3, we isolated the gene encoding the beta subunit of the human cGMP phosphodiesterase (PDEB). We formally assessed this as a candidate gene for HD based on it's expression in brain, the demonstration of linkage disequilibrium between intragenic DNA markers and HD, and the demonstration that mice with a mutation in this gene have a reduction of neurons in particular brain regions. We investigated all 22 exons of PDEB and 5'-flanking region for point mutations in 16 HD patients of different ethnic origins using single strand conformational polymorphism analysis. The underlying DNA changes found initially exclusively in HD patients were excluded as the cause for HD.
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3',5'-GMP Cíclico Fosfodiesterasas/genética , ADN/genética , Enfermedad de Huntington/enzimología , Enfermedad de Huntington/genética , Secuencia de Bases , Análisis Mutacional de ADN , Exones , Femenino , Reordenamiento Génico , Humanos , Masculino , Datos de Secuencia Molecular , Linaje , Fenotipo , Polimorfismo GenéticoRESUMEN
No detectable rearrangements involving chromosome 4p16.3 have been observed in patients with Huntington's disease (HD). New mutations for HD could involve structural alterations which might aid the localization of the defective gene. We have reinvestigated a well documented sporadic case of HD. DNA haplotyping with markers between D4S10 and the telomeric locus D4S141 reveals a recombination event in one chromosome of the sporadic HD patient. The site of recombination maps within a 50 kilobase (kb) region, about 700 kb from the 4p telomere. Based on the extremely low HD mutation rate and significantly decreased recombination in the distal region of 4p, we hypothesize a direct link between the site of the recombination and HD in this patient.
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Cromosomas Humanos Par 4 , Reordenamiento Génico/genética , Enfermedad de Huntington/genética , Recombinación Genética/genética , Adulto , Alelos , Secuencia de Bases , Niño , Mapeo Cromosómico , Paseo de Cromosoma , Clonación Molecular , Femenino , Marcadores Genéticos , Haplotipos/genética , Humanos , Masculino , Datos de Secuencia Molecular , Mutación/genética , Linaje , Polimorfismo Genético/genéticaRESUMEN
OBJECTIVE: While several genes have been identified to cause Parkinson's disease (PD), monogenic forms explain only a small proportion of cases. We report clinical and genetic results in a large family with late-onset autosomal dominant PD. METHODS: Thirty-eight family members of a five-generation Northern German PD family underwent a detailed neurologic examination, and transcranial sonography was performed in fifteen of them. Comprehensive mutation analysis of known PD-causing genes and a genome-wide linkage analysis were performed. RESULTS: Late-onset definite PD was found in five subjects with a mean age at onset of 63 years. Another six individuals presented either with probable/possible PD or with subtle parkinsonian signs. Six members with a mean age of 79 years had an essential tremor phenotype. Mode of PD inheritance was compatible with autosomal dominant transmission. One of three examined patients with definite PD demonstrated an increased area of substantia nigra hyperechogenicity upon transcranial sonography. Comprehensive linkage and mutational analysis excluded mutations in known PD-causing genes. Genome-wide linkage analysis suggested a putative disease gene in an 11.3-Mb region on chromosome 7p15-21.1 with a multipoint LOD score of 2.0. CONCLUSIONS: The findings in this family further demonstrate genetic heterogeneity in familial autosomal dominant late-onset PD.
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Trastornos Parkinsonianos/genética , Trastornos Parkinsonianos/patología , Edad de Inicio , Anciano , Encéfalo/patología , Análisis Mutacional de ADN , Femenino , Alemania , Humanos , Escala de Lod , Masculino , Persona de Mediana Edad , LinajeRESUMEN
Hereditary spastic paraplegia (HSP) is a neurodegenerative disorder defined clinically by progressive lower limb spasticity and weakness. HSP is a genetically highly heterogeneous condition with at least 46 gene loci identified so far, involving X-linked, autosomal recessive (AR) and autosomal dominant inheritance. For correct diagnosis, molecular testing is essential because clinical parameters by themselves are not reliable to differentiate HSP forms. The purpose of this study was to establish amplicon-based high-throughput genotyping for AR-HSP. A sample of 187 index cases with apparently sporadic or recessive spastic paraplegia were analyzed by applying an array-based amplification strategy. Amplicon libraries of the CYP7B1-(SPG5) and SPG7-gene were generated followed by a pooled next-generation sequencing (NGS) approach. We identified three SPG5 and seven SPG7 patients. All had one homozygous or two heterozygous mutations. In total, 20 distinct mutations (CYP7B1,n = 4and SPG7,n = 16) including two novel CYP7B1 mutations (p.G51R and p.E211KfsX3) and eight novel SPG7 mutations (p.Leu8delinsLeuLeu, p.W29X, p.R139X, p.R247X, p.G344D, p.Leu346_Leu347ins11, p.R398X and p.R398Q) were detected by this comprehensive genetic testing. Our study illustrates how amplicon-based NGS can be used as an efficient tool to study genotypes and mutations in large patient cohorts and complex phenotypes.
Asunto(s)
Análisis Mutacional de ADN/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Metaloendopeptidasas/genética , Mutación , Paraplejía/diagnóstico , Paraplejía/genética , Esteroide Hidroxilasas/genética , ATPasas Asociadas con Actividades Celulares Diversas , Secuencia de Bases , Estudios de Cohortes , Familia 7 del Citocromo P450 , Pruebas Genéticas , Variación Genética/genética , Genotipo , Humanos , Datos de Secuencia MolecularRESUMEN
Cone dystrophies are genetic diseases characterized by loss of cone photoreceptor function and severe impairment of daylight vision. Loss of function is accompanied by a progressive degeneration of cones limiting potential therapeutic interventions. In this study we combined microarray-based gene-expression analysis with electroretinography and immunohistochemistry to characterize the pathological processes in the cone photoreceptor function loss 1 (cpfl1) mouse model. The cpfl1-mouse is a naturally arising mouse mutant with a loss-of-function mutation in the cone-specific Pde6c gene. Cpfl1-mice displayed normal rod-specific light responses while cone-specific responses were strongly diminished. Despite the lack of a general retinal degeneration, the cone-specific functional defect resulted in a marked activation of GFAP, a hallmark of Müller-cell gliosis. Microarray-based network-analysis confirmed activation of Müller-glia-specific transcripts. Unexpectedly, we found up-regulation of the cytokine LIF and the anti-apoptotic transcription factor STAT3 in cpfl1 cone photoreceptors. We postulate that STAT3-related pathways are induced in cpfl1 cone photoreceptors to counteract degeneration.
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Regulación de la Expresión Génica , Células Fotorreceptoras Retinianas Conos/metabolismo , Degeneración Retiniana/genética , Factor de Transcripción STAT3/metabolismo , Animales , Ratones , Ratones Mutantes , Análisis de Secuencia por Matrices de Oligonucleótidos , Células Fotorreceptoras Retinianas Conos/patología , Degeneración Retiniana/patologíaRESUMEN
DYT1 dystonia is an autosomal-dominantly inherited movement disorder, which is usually caused by a GAG deletion in the TOR1A gene. Due to the reduced penetrance of approximately 30-40%, the determination of the mutation in a subject is of limited use with regard to actual manifestation of symptoms. In the present study, we used Affymetrix oligonucleotide microarrays to analyze global gene expression in blood samples of 15 manifesting and 15 non-manifesting mutation carriers in order to identify a susceptibility profile beyond the GAG deletion which is associated with the manifestation of symptoms in DYT1 dystonia. We identified a genetic signature which distinguished between asymptomatic mutation carriers and symptomatic DYT1 patients with 86.7% sensitivity and 100% specificity. This genetic signature could correctly predict the disease state in an independent test set with a sensitivity of 87.5% and a specificity of 85.7%. Conclusively, this genetic signature might provide a possibility to distinguish DYT1 patients from asymptomatic mutation carriers.
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Distonía Muscular Deformante/genética , Perfilación de la Expresión Génica , Chaperonas Moleculares/genética , Adulto , Femenino , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Humanos , Masculino , Persona de Mediana Edad , Mutación , Análisis de Secuencia por Matrices de Oligonucleótidos , Penetrancia , Repeticiones de TrinucleótidosRESUMEN
The European Union (EU) initiative on the Digital Transformation of Health and Care (Digicare) aims to provide the conditions necessary for building a secure, flexible, and decentralized digital health infrastructure. Creating a European Health Research and Innovation Cloud (HRIC) within this environment should enable data sharing and analysis for health research across the EU, in compliance with data protection legislation while preserving the full trust of the participants. Such a HRIC should learn from and build on existing data infrastructures, integrate best practices, and focus on the concrete needs of the community in terms of technologies, governance, management, regulation, and ethics requirements. Here, we describe the vision and expected benefits of digital data sharing in health research activities and present a roadmap that fosters the opportunities while answering the challenges of implementing a HRIC. For this, we put forward five specific recommendations and action points to ensure that a European HRIC: i) is built on established standards and guidelines, providing cloud technologies through an open and decentralized infrastructure; ii) is developed and certified to the highest standards of interoperability and data security that can be trusted by all stakeholders; iii) is supported by a robust ethical and legal framework that is compliant with the EU General Data Protection Regulation (GDPR); iv) establishes a proper environment for the training of new generations of data and medical scientists; and v) stimulates research and innovation in transnational collaborations through public and private initiatives and partnerships funded by the EU through Horizon 2020 and Horizon Europe.
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Investigación Biomédica/organización & administración , Nube Computacional , Difusión de Innovaciones , Guías de Práctica Clínica como Asunto , Investigación Biomédica/métodos , Unión Europea , Difusión de la Información/legislación & jurisprudencia , Difusión de la Información/métodosRESUMEN
BACKGROUND: Hereditary spastic paraplegias (HSP) are clinically and genetically highly heterogeneous. Recently, two novel genes, SPG11 (spatacsin) and SPG15 (spastizin), associated with autosomal recessive HSP, were identified. Clinically, both are characterised by complicated HSP and a rather similar phenotype consisting of early onset spastic paraplegia, cognitive deficits, thin corpus callosum (TCC), peripheral neuropathy and mild cerebellar ataxia. OBJECTIVE: To compare the frequency of SPG11 and SPG15 in patients with early onset complicated HSP and to further characterise the phenotype of SPG11 and SPG15. RESULTS: A sample of 36 index patients with early onset complicated HSP and a family history compatible with autosomal recessive inheritance was collected and screened for mutations in SPG11 and SPG15. Overall frequency of SPG11 was 14% (5/36) but was considerably higher in patients with TCC (42%). One patient with mental retardation and thinning of the corpus callosum was compound heterozygous for two novel SPG15 mutations. Additionally, several new polymorphisms and sequence variants of unknown significance have been identified in the SPG15 gene. CONCLUSIONS: TCC seems to be the best phenotypic predictor for SPG11 as well as SPG15. No clinical features could discriminate between SPG11 and SPG15. Therefore, priority of genetic testing should be driven by mutation frequency that appears to be substantially higher in SPG11 than in SPG15.
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Proteínas Portadoras/genética , Proteínas/genética , Paraplejía Espástica Hereditaria/genética , Adolescente , Adulto , Cuerpo Calloso/patología , Femenino , Frecuencia de los Genes , Genes Recesivos/genética , Estudios de Asociación Genética , Humanos , Discapacidad Intelectual/genética , Masculino , Mutación , Fenotipo , Polimorfismo Genético/genética , Adulto JovenRESUMEN
The protein leucine-rich repeat kinase 2 (LRRK2) is a key player in the pathogenesis of Parkinson's disease (PD). Mutations in the LRRK2 gene account for up to 10% of all autosomal dominant forms of familiar and for approximately 1-3% of sporadic PD patients. Although the LRRK2 protein has many functional domains like a leucine-rich repeat domain, a Roc-GTPase domain, a kinase domain of the tyrosine kinase-like subfamily and multiple protein interaction domains (armadillo, ankyrin, WD40), the exact biological role of LRRK2 in the human brain is elusive. To gain more insight into the biological function of this protein, we monitored the changes in the expression profiles of SH-SY5Y cells, a dopaminergic neuroblastoma cell line, induced by a depletion of LRRK2 levels by RNA interference (RNAi) with Affymetrix U133 Plus 2.0 microarrays. A total of 187 genes were differentially regulated by at least a 1.5-fold change with 94 transcripts being upregulated and 93 transcripts being downregulated compared to scrambled control siRNA transfected cells. Key players of the interaction networks were independently verified by qRT-PCR. The differentially expressed gene products are involved in axonal guidance, nervous system development, cell cycle, cell growth, cell differentiation, cell communication, MAPKKK cascade, and Ras protein signal transduction. Defined gene expression networks will now serve to look more closely for candidates affected by LRRK2 reduction and how they might be altered in other forms of familial or sporadic PD.
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Enfermedad de Parkinson/enzimología , Enfermedad de Parkinson/genética , Proteínas Serina-Treonina Quinasas/genética , Interferencia de ARN , Secuencia de Bases , Línea Celular , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Modelos Genéticos , Mutación , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , ARN Interferente Pequeño/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de SeñalAsunto(s)
Anomalías Múltiples/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Mutación , Intercambiadores de Sodio-Hidrógeno/genética , Anomalías Múltiples/patología , Ataxia/patología , Análisis Mutacional de ADN , Salud de la Familia , Femenino , Enfermedades Genéticas Ligadas al Cromosoma X/patología , Predisposición Genética a la Enfermedad/genética , Humanos , Discapacidad Intelectual/patología , Masculino , Microcefalia/patología , Linaje , Convulsiones/patología , Factores Sexuales , SíndromeRESUMEN
BACKGROUND: The three-nucleotide deletion, triangle upGAG (within the gene TOR1A), is the only proven cause of childhood-onset dystonia (DYT1). A potentially pathogenic role of additional sequence changes within TOR1A has not been conclusively shown. METHODS: DNA sequencing of exon 5 of TOR1A in a patient with DYT1. RESULTS: Detection of sequence change c.863G>A in exon 5 of TOR1A in the patient. The G>A transition results in an exchange of an arginine for glutamine (p.Arg288Gln) in subdomain alpha5 of TOR1A. Several findings point to a potentially pathogenic role of the sequence change in the patient: The base change is absent in 1000 control chromosomes; an Arg at position 288 of TOR1A has been conserved throughout vertebrate evolution, indicating an important role of Arg288 in TOR1A function; functional studies demonstrate enlarged perinuclear space in HEK293 cells overexpressing TOR1A with the p.Arg288Gln mutation. The same morphological changes are observed in cells overexpressing the common triangle upGAG TOR1A mutation but not in cells overexpressing wild-type TOR1A. CONCLUSIONS: The sequence change described here may be a novel pathogenic mutation of TOR1A in DYT1.
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Trastornos Distónicos/diagnóstico , Trastornos Distónicos/genética , Chaperonas Moleculares/genética , Mutación , Adolescente , Secuencia de Aminoácidos , Núcleo Celular/metabolismo , Trastornos de Deglución/diagnóstico , Trastornos de Deglución/genética , Progresión de la Enfermedad , Exones , Femenino , Humanos , Microscopía Electrónica , Datos de Secuencia Molecular , Análisis de Secuencia de ADN , Homología de Secuencia de AminoácidoAsunto(s)
Alanina , Proteínas del Tejido Nervioso/genética , Enfermedad de Parkinson/genética , Mutación Puntual , Prolina , Secuencia de Aminoácidos , Secuencia de Bases , Femenino , Humanos , Masculino , Proteínas del Tejido Nervioso/química , Linaje , Polimorfismo Conformacional Retorcido-Simple , Sinucleínas , alfa-SinucleínaAsunto(s)
Repeticiones de Minisatélite , Ataxias Espinocerebelosas/genética , Repeticiones de Trinucleótidos , Regiones no Traducidas 5' , Adulto , Alelos , Secuencia de Bases , Cartilla de ADN/genética , Femenino , Genes Dominantes , Ligamiento Genético , Humanos , Masculino , Persona de Mediana Edad , LinajeRESUMEN
Among full autosomal trisomies, only trisomies of chromosome 21 (Down syndrome), 18 (Edwards syndrome) and 13 (Patau syndrome) are compatible with postnatal survival. But the mechanisms, how a supernumerary chromosome disrupts the normal development and causes specific phenotypes, are still not fully explained. As an alternative to gene dosage effect due to the trisomic chromosome a genome-wide transcriptional dysregulation has been postulated. The aim of this study was to define the transcriptional changes in trisomy 13, 18, and 21 during early fetal development in order to obtain more insights into the molecular etiopathology of aneuploidy. Using oligonucleotide microarrays, we analyzed whole genome expression profiles in cultured amniocytes (AC) and chorionic villus cells (CV) from pregnancies with a normal karyotype and with trisomies of human chromosomes 13, 18 and 21. We observed a low to moderate up-regulation for a subset of genes of the trisomic chromosomes. Transcriptional levels of most of the genes on the supernumerary chromosome appeared similar to the respective chromosomal pair in normal karyotypes. A subset of chromosome 21 genes including the DSCR1 gene involved in fetal heart development was consistently up-regulated in different prenatal tissues (AC, CV) of trisomy 21 fetuses whereas only minor changes were found for genes of all other chromosomes. In contrast, in trisomy 18 vigorous downstream transcriptional changes were found. Global transcriptome analysis for autosomal trisomies 13, 18, and 21 supported a combination of the two major hypotheses.
Asunto(s)
Cromosomas Humanos/genética , Feto/metabolismo , Regulación del Desarrollo de la Expresión Génica , Transcripción Genética , Trisomía/genética , Amnios/citología , Amnios/metabolismo , Células Cultivadas , Vellosidades Coriónicas/metabolismo , Cromosomas Humanos Par 13/genética , Cromosomas Humanos Par 18/genética , Cromosomas Humanos Par 21/genética , Femenino , Perfilación de la Expresión Génica , Genes del Desarrollo , Humanos , Embarazo , Análisis de Componente Principal , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reproducibilidad de los Resultados , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by a CAG repeat expansion in the HD gene. Excitotoxic cell damage by excessive stimulation of glutamate receptors has been hypothesized to contribute to the pathogenesis of HD. Transgenic mouse models of HD have shown variable sensitivity to excitotoxicity. The models differ in the genetic background, the type and length of the promoter driving the transgene expression, the CAG repeat length and/or the HD gene construct length. Furthermore, one has to differentiate whether transgenic or knock-in models have been used. All these factors may be involved in determining the responsiveness to an excitotoxic insult. Here, we explored the responsiveness to excitotoxic damage using a transgenic HD rat model carrying 22% of the rat HD gene which is driven by the rat HD promoter and which harbors 51 CAG repeats. 3 and 18 months old transgenic HD rats and their wild-type littermates received unilateral intrastriatal injections of the glutamate analogue quinolinic acid. Lesion size was assessed 7 days later using the degenerative stain Fluoro-Jade and by immunohistochemistry for the neuronal protein NeuN. No difference in susceptibility to excitotoxicity was found between the groups. Our study supports mouse data showing maintained susceptibility to excitotoxicity with the expression of around 25% of the full HD gene. Differences in sensitivity to excitotoxicity between genetic animal models of HD may be dependent on the length of the expressed HD gene although additional factors are also likely to be important.