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1.
Nat Genet ; 51(3): 387-393, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30804566

RESUMO

Insomnia is a common disorder linked with adverse long-term medical and psychiatric outcomes. The underlying pathophysiological processes and causal relationships of insomnia with disease are poorly understood. Here we identified 57 loci for self-reported insomnia symptoms in the UK Biobank (n = 453,379) and confirmed their effects on self-reported insomnia symptoms in the HUNT Study (n = 14,923 cases and 47,610 controls), physician-diagnosed insomnia in the Partners Biobank (n = 2,217 cases and 14,240 controls), and accelerometer-derived measures of sleep efficiency and sleep duration in the UK Biobank (n = 83,726). Our results suggest enrichment of genes involved in ubiquitin-mediated proteolysis and of genes expressed in multiple brain regions, skeletal muscle, and adrenal glands. Evidence of shared genetic factors was found between frequent insomnia symptoms and restless legs syndrome, aging, and cardiometabolic, behavioral, psychiatric, and reproductive traits. Evidence was found for a possible causal link between insomnia symptoms and coronary artery disease, depressive symptoms, and subjective well-being.


Assuntos
Predisposição Genética para Doença/genética , Distúrbios do Início e da Manutenção do Sono/genética , Sono/genética , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Expressão Gênica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Proteólise , Autorrelato , Ubiquitina/genética
2.
Nervenarzt ; 90(2): 131-137, 2019 Feb.
Artigo em Alemão | MEDLINE | ID: mdl-30645660

RESUMO

After an impressively successful application as a research instrument, whole-exome sequencing (WES) now enters the clinical practice due to its high diagnostic, time, and economic efficiency. WES is the diagnostic method of choice for symptoms that may be due to many different monogenic causes. Neurological indications include movement disorders, especially in cases of early symptom onset, familial clustering and complex manifestation. Starting from a blood sample, enrichment and sequencing of the exome enable the examination of all coding DNA regions for point mutations and small insertions/deletions. The identification of variants as the cause of a disease requires a professional evaluation pipeline, variant prioritization schemes and variant classification databases. Whereas many variants can be reliably classified as pathogenic or benign, variants of unclear significance (VUS) remain a challenge for the clinical evaluation and necessitate a periodic reanalysis of WES data. As a genetic examination WES requires adequate patient informed consent which in particular should address possible secondary findings as well as data security. A positive molecular result ends diagnostic odysseys, enables accurate genetic counseling and can point to targeted preventive measures and treatment. A WES significantly contributes to the understanding of the genetic architecture and pathophysiology of neurological diseases, enriching and enabling precision medicine.


Assuntos
Exoma , Testes Genéticos , Doenças do Sistema Nervoso , Neurologia , Exoma/genética , Humanos , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/genética , Neurologia/tendências , Sequenciamento Completo do Exoma
3.
Lancet Neurol ; 17(11): 994-1005, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30244828

RESUMO

Restless legs syndrome, also known as Willis-Ekbom disease, is a common neurological condition whose manifestation is affected by complex environmental and genetic interactions. Restless legs syndrome can occur on its own, mostly at a young age, or with comorbidities such as cardiovascular disease, diabetes, and arterial hypertension, making it a difficult condition to properly diagnose. However, the concept of restless legs syndrome as being two entities, primary or secondary to another condition, has been challenged with genetic data providing further insight into the pathophysiology of the condition. Although dopaminergic treatment was formerly the first-line therapy, prolonged use can result in a serious worsening of symptoms known as augmentation. Clinical studies on pregabalin, gabapentin enacarbil, oxycodone-naloxone, and iron preparations have provided new treatment options, but most patients still report inadequate long-term management of symptoms. Studies of the hypoxic pathway activation and iron deficiency have provided valuable information about the pathophysiology of restless legs syndrome that should now be translated into new, more effective treatments for restless legs syndrome.

4.
J Sleep Res ; 27(4): e12557, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28695622

RESUMO

Meis homeobox 1 (Meis1) is a transcription factor functioning in the development of the nervous system and the cardiovascular system. Both common and rare variants within the gene have been associated with restless legs syndrome (RLS), while its association with symptoms of insomnia has also been discovered recently. RLS is associated with sleep disturbances, and while Meis1 haploinsufficiency is one of the most promising strategies for an RLS animal model, sleep phenotyping of Meis1 knockout mice has never been conducted. We report a detailed sleep analysis of heterozygous Meis1 knockout mice and challenge it with pramipexole, a dopamine agonist used in the treatment of RLS. At baseline, the Meis1-haploinsufficient mice had a trend towards lower delta power in the electroencephalogram (EEG) during sleep compared to the wild-type littermates, possibly indicating reduced sleep quality, but not sleep fragmentation. Pramipexole had a sleep disrupting effect in both genotype groups. In addition, it exerted differential effects on the EEG power spectra of the two mouse lines, remarkably elevating the theta power of the mutant mice during recovery more than that of the wild-types. In conclusion, Meis1 haploinsufficiency seems to have only a modest effect on sleep, but the gene may interact with the sleep-disrupting effect of dopamine agonists.

5.
Lancet Neurol ; 16(11): 898-907, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29029846

RESUMO

BACKGROUND: Restless legs syndrome is a prevalent chronic neurological disorder with potentially severe mental and physical health consequences. Clearer understanding of the underlying pathophysiology is needed to improve treatment options. We did a meta-analysis of genome-wide association studies (GWASs) to identify potential molecular targets. METHODS: In the discovery stage, we combined three GWAS datasets (EU-RLS GENE, INTERVAL, and 23andMe) with diagnosis data collected from 2003 to 2017, in face-to-face interviews or via questionnaires, and involving 15 126 cases and 95 725 controls of European ancestry. We identified common variants by fixed-effect inverse-variance meta-analysis. Significant genome-wide signals (p≤5 × 10-8) were tested for replication in an independent GWAS of 30 770 cases and 286 913 controls, followed by a joint analysis of the discovery and replication stages. We did gene annotation, pathway, and gene-set-enrichment analyses and studied the genetic correlations between restless legs syndrome and traits of interest. FINDINGS: We identified and replicated 13 new risk loci for restless legs syndrome and confirmed the previously identified six risk loci. MEIS1 was confirmed as the strongest genetic risk factor for restless legs syndrome (odds ratio 1·92, 95% CI 1·85-1·99). Gene prioritisation, enrichment, and genetic correlation analyses showed that identified pathways were related to neurodevelopment and highlighted genes linked to axon guidance (associated with SEMA6D), synapse formation (NTNG1), and neuronal specification (HOXB cluster family and MYT1). INTERPRETATION: Identification of new candidate genes and associated pathways will inform future functional research. Advances in understanding of the molecular mechanisms that underlie restless legs syndrome could lead to new treatment options. We focused on common variants; thus, additional studies are needed to dissect the roles of rare and structural variations. FUNDING: Deutsche Forschungsgemeinschaft, Helmholtz Zentrum München-Deutsches Forschungszentrum für Gesundheit und Umwelt, National Research Institutions, NHS Blood and Transplant, National Institute for Health Research, British Heart Foundation, European Commission, European Research Council, National Institutes of Health, National Institute of Neurological Disorders and Stroke, NIH Research Cambridge Biomedical Research Centre, and UK Medical Research Council.


Assuntos
Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Síndrome das Pernas Inquietas/epidemiologia , Síndrome das Pernas Inquietas/genética , Proteínas de Ligação a DNA/genética , Grupo com Ancestrais do Continente Europeu , Proteínas Ligadas por GPI/genética , Humanos , Proteínas do Tecido Nervoso/genética , Netrinas , Semaforinas/genética , Fatores de Transcrição/genética
6.
Nat Genet ; 49(11): 1584-1592, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28604731

RESUMO

Persistent insomnia is among the most frequent complaints in general practice. To identify genetic factors for insomnia complaints, we performed a genome-wide association study (GWAS) and a genome-wide gene-based association study (GWGAS) in 113,006 individuals. We identify three loci and seven genes associated with insomnia complaints, with the associations for one locus and five genes supported by joint analysis with an independent sample (n = 7,565). Our top association (MEIS1, P < 5 × 10-8) has previously been implicated in restless legs syndrome (RLS). Additional analyses favor the hypothesis that MEIS1 exhibits pleiotropy for insomnia and RLS and show that the observed association with insomnia complaints cannot be explained only by the presence of an RLS subgroup within the cases. Sex-specific analyses suggest that there are different genetic architectures between the sexes in addition to shared genetic factors. We show substantial positive genetic correlation of insomnia complaints with internalizing personality traits and metabolic traits and negative correlation with subjective well-being and educational attainment. These findings provide new insight into the genetic architecture of insomnia.


Assuntos
Redes Reguladoras de Genes , Loci Gênicos , Predisposição Genética para Doença , Genoma Humano , Proteínas de Homeodomínio/genética , Proteínas de Neoplasias/genética , Distúrbios do Início e da Manutenção do Sono/genética , Adulto , Alelos , Mapeamento Cromossômico , Escolaridade , Feminino , Expressão Gênica , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Masculino , Proteína Meis1 , Polimorfismo de Nucleotídeo Único , Mapeamento de Interação de Proteínas , Qualidade de Vida/psicologia , Síndrome das Pernas Inquietas/genética , Síndrome das Pernas Inquietas/metabolismo , Síndrome das Pernas Inquietas/fisiopatologia , Síndrome das Pernas Inquietas/psicologia , Fatores Sexuais , Distúrbios do Início e da Manutenção do Sono/metabolismo , Distúrbios do Início e da Manutenção do Sono/fisiopatologia , Distúrbios do Início e da Manutenção do Sono/psicologia , Personalidade Tipo D
7.
Dis Model Mech ; 10(8): 981-991, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28645892

RESUMO

MEIS1 encodes a developmental transcription factor and has been linked to restless legs syndrome (RLS) in genome-wide association studies. RLS is a movement disorder leading to severe sleep reduction and has a substantial impact on the quality of life of patients. In genome-wide association studies, MEIS1 has consistently been the gene with the highest effect size and functional studies suggest a disease-relevant downregulation. Therefore, haploinsufficiency of Meis1 could be the system with the most potential for modeling RLS in animals. We used heterozygous Meis1-knockout mice to study the effects of Meis1 haploinsufficiency on mouse behavioral and neurological phenotypes, and to relate the findings to human RLS. We exposed the Meis1-deficient mice to assays of motor, sensorimotor and cognitive ability, and assessed the effect of a dopaminergic receptor 2/3 agonist commonly used in the treatment of RLS. The mutant mice showed a pattern of circadian hyperactivity, which is compatible with human RLS. Moreover, we discovered a replicable prepulse inhibition (PPI) deficit in the Meis1-deficient animals. In addition, these mice were hyposensitive to the PPI-reducing effect of the dopaminergic receptor agonist, highlighting a role of Meis1 in the dopaminergic system. Other reported phenotypes include enhanced social recognition at an older age that was not related to alterations in adult olfactory bulb neurogenesis previously shown to be implicated in this behavior. In conclusion, the Meis1-deficient mice fulfill some of the hallmarks of an RLS animal model, and revealed the role of Meis1 in sensorimotor gating and in the dopaminergic systems modulating it.


Assuntos
Proteína Meis1/metabolismo , Córtex Sensório-Motor/metabolismo , Córtex Sensório-Motor/patologia , Envelhecimento/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Neurônios Dopaminérgicos/metabolismo , Feminino , Ferritinas/sangue , Haploinsuficiência/genética , Ferro/sangue , Masculino , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Proteína Meis1/deficiência , Neurogênese/efeitos dos fármacos , Nociceptividade/efeitos dos fármacos , Fenótipo , Inibição Pré-Pulso/efeitos dos fármacos , Receptores Dopaminérgicos/metabolismo , Córtex Sensório-Motor/efeitos dos fármacos , Filtro Sensorial/efeitos dos fármacos , Caracteres Sexuais , Temperatura Ambiente , Transferrina/metabolismo
8.
Sleep Med ; 31: 18-22, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28065402

RESUMO

At the outset of genetic studies in restless legs syndrome (RLS), the disorder was assumed to be a classical monogenic disorder that runs in families. However, years of family studies did not reveal any causally-related genes or genetic variants. The advent of high-throughput genotyping technology led to a change; genome-wide association studies in large case-control samples became feasible, which led to the identification of first genetic risk variants for RLS. Variants detected by this approach are common ones, which that individually confer only a minor increase in risk of disease. Overall, the currently known risk variants in six genomic loci account for only a small proportion of the genetically determined susceptibility to RLS. Additional risk loci and individual variants remain to be discovered. First studies indicate that rare genetic variants are also important contributors in RLS. These are expected to have a larger impact on the phenotype and may thus prove to be excellent candidates for functional studies and, in the long-term, targets for developing therapeutics or preventive measures. To enable their discovery, large-scale studies including tens of thousands of affected individuals may be needed. Next-generation sequencing technologies such as whole exome or whole genome sequencing will be essential for this endeavor. Even though the number of known risk variants is still limited, they have been indispensable in terms of deciphering the underlying pathophysiology of RLS, providing the molecular starting points for animal models and in vitro studies to understand disease mechanisms. In addition, genetic risk variants can be valuable tools for disentangling the phenotypic complexity observed in RLS. Testing RLS risk variants for associations with periodic limb movements (PLMs) identified a significant role of some of the variants and suggested PLMs as an endophenotype in RLS. Further advances in genetics research in RLS will be driven by large-scale sequencing projects and the identification of additional common, but also rarer risk variants with larger effects on disease risk. Another uncharted territory in RLS research epigenetic effect on gene activity. Overall, genetic studies continue to hold great potential for understanding biology of the disease.


Assuntos
Síndrome das Pernas Inquietas/genética , Animais , Humanos , Síndrome das Pernas Inquietas/metabolismo
9.
Mov Disord ; 32(4): 549-559, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27666935

RESUMO

BACKGROUND: Dystonia is clinically and genetically heterogeneous. Despite being a first-line testing tool for heterogeneous inherited disorders, whole-exome sequencing has not yet been evaluated in dystonia diagnostics. We set up a pilot study to address the yield of whole-exome sequencing for early-onset generalized dystonia, a disease subtype enriched for monogenic causation. METHODS: Clinical whole-exome sequencing coupled with bioinformatics analysis and detailed phenotyping of mutation carriers was performed on 16 consecutive cases with genetically undefined early-onset generalized dystonia. Candidate pathogenic variants were validated and tested for cosegregation. The whole-exome approach was complemented by analyzing 2 mutated yet unestablished causative genes in another 590 dystonia cases. RESULTS: Whole-exome sequencing detected clinically relevant mutations of known dystonia-related genes in 6 generalized dystonia cases (37.5%), among whom 3 had novel variants. Reflecting locus heterogeneity, identified unique variants were distributed over 5 genes (GCH1, THAP1, TOR1A, ANO3, ADCY5), of which only 1 (ANO3) was mutated recurrently. Three genes (GCH1, THAP1, TOR1A) were associated with isolated generalized dystonia, whereas 2 (ANO3, ADCY5) gave rise to combined dystonia-myoclonus phenotypes. Follow-up screening of ANO3 and ADCY5 revealed a set of distinct variants of interest, the pathogenicity of which was supported by bioinformatics testing and cosegregation work. CONCLUSIONS: Our study identified whole-exome sequencing as an effective strategy for molecular diagnosis of early-onset generalized dystonia and offers insights into the heterogeneous genetic architecture of this condition. Furthermore, it provides confirmatory evidence for a dystonia-relevant role of ANO3 and ADCY5, both of which likely associate with a broader spectrum of dystonic expressions than previously thought. © 2016 International Parkinson and Movement Disorder Society.


Assuntos
Distonia/genética , Exoma/genética , Mutação/genética , Adenilil Ciclases/genética , Adulto , Anoctaminas , Proteínas Reguladoras de Apoptose/genética , Canais de Cloreto/genética , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Saúde da Família , Feminino , Seguimentos , GTP Cicloidrolase/genética , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Chaperonas Moleculares/genética , Proteínas Nucleares/genética , Adulto Jovem
10.
Am J Hum Genet ; 96(6): 883-93, 2015 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-26004199

RESUMO

Isolated dystonia is a disorder characterized by involuntary twisting postures arising from sustained muscle contractions. Although autosomal-dominant mutations in TOR1A, THAP1, and GNAL have been found in some cases, the molecular mechanisms underlying isolated dystonia are largely unknown. In addition, although emphasis has been placed on dominant isolated dystonia, the disorder is also transmitted as a recessive trait, for which no mutations have been defined. Using whole-exome sequencing in a recessive isolated dystonia-affected kindred, we identified disease-segregating compound heterozygous mutations in COL6A3, a collagen VI gene associated previously with muscular dystrophy. Genetic screening of a further 367 isolated dystonia subjects revealed two additional recessive pedigrees harboring compound heterozygous mutations in COL6A3. Strikingly, all affected individuals had at least one pathogenic allele in exon 41, including an exon-skipping mutation that induced an in-frame deletion. We tested the hypothesis that disruption of this exon is pathognomonic for isolated dystonia by inducing a series of in-frame deletions in zebrafish embryos. Consistent with our human genetics data, suppression of the exon 41 ortholog caused deficits in axonal outgrowth, whereas suppression of other exons phenocopied collagen deposition mutants. All recessive mutation carriers demonstrated early-onset segmental isolated dystonia without muscular disease. Finally, we show that Col6a3 is expressed in neurons, with relevant mRNA levels detectable throughout the adult mouse brain. Taken together, our data indicate that loss-of-function mutations affecting a specific region of COL6A3 cause recessive isolated dystonia with underlying neurodevelopmental deficits and highlight the brain extracellular matrix as a contributor to dystonia pathogenesis.


Assuntos
Colágeno Tipo VI/genética , Distúrbios Distônicos/genética , Distúrbios Distônicos/patologia , Variação Genética , Animais , Sequência de Bases , Biologia Computacional , Análise Mutacional de DNA , Exoma/genética , Genes Recessivos , Testes Genéticos , Hibridização In Situ , Imagem por Ressonância Magnética , Camundongos , Dados de Sequência Molecular , Músculo Esquelético , Mutação/genética , Linhagem , Peixe-Zebra/genética
11.
Sleep ; 37(10): 1601-8, 2014 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-25197808

RESUMO

STUDY OBJECTIVES: To identify rare allelic variants and HLA alleles in narcolepsy patients with hypocretin (orexin, HCRT) deficiency but lacking DQB1*06:02. SETTINGS: China (Peking University People's Hospital), Czech Republic (Charles University), Denmark (Golstrup Hospital), Italy (University of Bologna), Korea (Catholic University), and USA (Stanford University). DESIGN: CSF hypocretin-1, DQB1*06:02, clinical and polysomnographic data were collected in narcolepsy patients (552 with and 144 without cataplexy) from 6 sites. Numbers of cases with and without DQB1*06:02 and low CSF hypocretin-1 were compiled. HLA class I (A, B, C), class II (DRBs, DQA1, DQB1, DPA1, and DPB1), and whole exome sequencing were conducted in 9 DQB1*06:02 negative cases with low CSF hypocretin-1. Sanger sequencing of selected exons in DNMT1, HCRT, and MOG was performed to exclude mutations in known narcolepsy-associated genes. MEASUREMENTS AND RESULTS: Classic narcolepsy markers DQB1*06:02 and low CSF hypocretin-1 were found in 87.4% of cases with cataplexy, and in 20.0% without cataplexy. Nine cases (all with cataplexy) were DQB1*06:02 negative with low CSF hypocretin-1, constituting 1.7% [0.8%-3.4%] of all cases with cataplexy and 1.8% [0.8%-3.4%] of cases with low CSF hypocretin independent of cataplexy across sites. Five HLA negative subjects had severe cataplexy, often occurring without clear triggers. Subjects had diverse ethnic backgrounds and HLA alleles at all loci, suggesting no single secondary HLA association. The rare subtype DPB1*0901, and homologous DPB1*10:01 subtype, were present in 5 subjects, suggesting a secondary association with HLA-DP. Preprohypocretin sequencing revealed no mutations beyond one previously reported in a very early onset case. No new MOG or DNMT1 mutations were found, nor were suspicious or private variants in novel genes identified through exome sequencing. CONCLUSIONS: Hypocretin, MOG, or DNMT1 mutations are exceptional findings in DQB1*06:02 negative cases with hypocretin deficiency. A secondary HLA-DP association may be present in these cases. These represent particularly difficult diagnostic challenges.


Assuntos
Cadeias beta de HLA-DQ/genética , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Peptídeos e Proteínas de Sinalização Intracelular/genética , Narcolepsia/genética , Neuropeptídeos/deficiência , Neuropeptídeos/genética , Alelos , Cataplexia/genética , Estudos de Coortes , Análise Mutacional de DNA , Humanos , Internacionalidade , Peptídeos e Proteínas de Sinalização Intracelular/líquido cefalorraquidiano , Mutação/genética , Glicoproteína Mielina-Oligodendrócito/genética , Neuropeptídeos/líquido cefalorraquidiano , Orexinas , Proteínas Repressoras/genética
12.
Mov Disord ; 29(12): 1504-10, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25142429

RESUMO

Recessive DYT16 dystonia associated with mutations in PRKRA has until now been reported only in seven Brazilian patients. The aim of this study was to elucidate the genetic cause underlying disease in a Polish family with autosomal-recessive, early-onset generalized dystonia and slight parkinsonism, and to explore further the role of PRKRA in a dystonia series of European ancestry. We employed whole-exome sequencing in two affected siblings of the Polish family and filtered for rare homozygous and compound heterozygous variants shared by both exomes. Validation of the identified variants as well as homozygosity screening and copy number variation analysis was carried out in the two affected individuals and their healthy siblings. PRKRA was analyzed in 339 German patients with various forms of dystonia and 376 population-based controls by direct sequencing or high-resolution melting. The previously described homozygous p.Pro222Leu mutation in PRKRA was found to segregate with the disease in the studied family, contained in a 1.2 Mb homozygous region identical by state with all Brazilian patients in chromosome 2q31.2. The clinical presentation with young-onset, progressive generalized dystonia and mild parkinsonism resembled the phenotype of the original DYT16 cases. PRKRA mutational screening in additional dystonia samples revealed three novel heterozygous changes (p.Thr34Ser, p.Asn102Ser, c.-14A>G), each in a single subject with focal/segmental dystonia. Our study provides the first independent replication of the DYT16 locus at 2q31.2 and strongly confirms the causal contribution of the PRKRA gene to DYT16. Our data suggest worldwide involvement of PRKRA in dystonia.


Assuntos
Variações do Número de Cópias de DNA/genética , Distúrbios Distônicos/genética , Exoma/genética , Saúde da Família , Proteínas de Ligação a RNA/genética , Adolescente , Adulto , Criança , Cromossomos Humanos Par 2/genética , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Índice de Gravidade de Doença , Adulto Jovem
13.
Genome Res ; 24(4): 592-603, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24642863

RESUMO

Genome-wide association studies (GWAS) identified the MEIS1 locus for Restless Legs Syndrome (RLS), but causal single nucleotide polymorphisms (SNPs) and their functional relevance remain unknown. This locus contains a large number of highly conserved noncoding regions (HCNRs) potentially functioning as cis-regulatory modules. We analyzed these HCNRs for allele-dependent enhancer activity in zebrafish and mice and found that the risk allele of the lead SNP rs12469063 reduces enhancer activity in the Meis1 expression domain of the murine embryonic ganglionic eminences (GE). CREB1 binds this enhancer and rs12469063 affects its binding in vitro. In addition, MEIS1 target genes suggest a role in the specification of neuronal progenitors in the GE, and heterozygous Meis1-deficient mice exhibit hyperactivity, resembling the RLS phenotype. Thus, in vivo and in vitro analysis of a common SNP with small effect size showed allele-dependent function in the prospective basal ganglia representing the first neurodevelopmental region implicated in RLS.


Assuntos
Elementos Facilitadores Genéticos , Proteínas de Homeodomínio/genética , Proteínas de Neoplasias/genética , Síndrome das Pernas Inquietas/genética , Telencéfalo/crescimento & desenvolvimento , Alelos , Animais , Gânglios da Base/metabolismo , Gânglios da Base/patologia , Modelos Animais de Doenças , Estudo de Associação Genômica Ampla , Íntrons , Camundongos , Proteína Meis1 , Polimorfismo de Nucleotídeo Único , Telencéfalo/patologia
14.
N Engl J Med ; 370(10): 921-31, 2014 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-24552285

RESUMO

BACKGROUND: Polyarteritis nodosa is a systemic necrotizing vasculitis with a pathogenesis that is poorly understood. We identified six families with multiple cases of systemic and cutaneous polyarteritis nodosa, consistent with autosomal recessive inheritance. In most cases, onset of the disease occurred during childhood. METHODS: We carried out exome sequencing in persons from multiply affected families of Georgian Jewish or German ancestry. We performed targeted sequencing in additional family members and in unrelated affected persons, 3 of Georgian Jewish ancestry and 14 of Turkish ancestry. Mutations were assessed by testing their effect on enzymatic activity in serum specimens from patients, analysis of protein structure, expression in mammalian cells, and biophysical analysis of purified protein. RESULTS: In all the families, vasculitis was caused by recessive mutations in CECR1, the gene encoding adenosine deaminase 2 (ADA2). All the Georgian Jewish patients were homozygous for a mutation encoding a Gly47Arg substitution, the German patients were compound heterozygous for Arg169Gln and Pro251Leu mutations, and one Turkish patient was compound heterozygous for Gly47Val and Trp264Ser mutations. In the endogamous Georgian Jewish population, the Gly47Arg carrier frequency was 0.102, which is consistent with the high prevalence of disease. The other mutations either were found in only one family member or patient or were extremely rare. ADA2 activity was significantly reduced in serum specimens from patients. Expression in human embryonic kidney 293T cells revealed low amounts of mutant secreted protein. CONCLUSIONS: Recessive loss-of-function mutations of ADA2, a growth factor that is the major extracellular adenosine deaminase, can cause polyarteritis nodosa vasculopathy with highly varied clinical expression. (Funded by the Shaare Zedek Medical Center and others.).


Assuntos
Adenosina Desaminase/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Mutação , Poliarterite Nodosa/genética , Adenosina Desaminase/química , Adenosina Desaminase/metabolismo , Adolescente , Idade de Início , Criança , Pré-Escolar , Exoma , Feminino , Genes Recessivos , República da Geórgia , Humanos , Lactente , Peptídeos e Proteínas de Sinalização Intercelular/química , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Judeus/genética , Masculino , Pessoa de Meia-Idade , Linhagem , Poliarterite Nodosa/patologia , Turquia
15.
Neurogenetics ; 15(1): 49-57, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24241507

RESUMO

Approximately 20 % of individuals with Parkinson's disease (PD) report a positive family history. Yet, a large portion of causal and disease-modifying variants is still unknown. We used exome sequencing in two affected individuals from a family with late-onset PD to identify 15 potentially causal variants. Segregation analysis and frequency assessment in 862 PD cases and 1,014 ethnically matched controls highlighted variants in EEF1D and LRRK1 as the best candidates. Mutation screening of the coding regions of these genes in 862 cases and 1,014 controls revealed several novel non-synonymous variants in both genes in cases and controls. An in silico multi-model bioinformatics analysis was used to prioritize identified variants in LRRK1 for functional follow-up. However, protein expression, subcellular localization, and cell viability were not affected by the identified variants. Although it has yet to be proven conclusively that variants in LRRK1 are indeed causative of PD, our data strengthen a possible role for LRRK1 in addition to LRRK2 in the genetic underpinnings of PD but, at the same time, highlight the difficulties encountered in the study of rare variants identified by next-generation sequencing in diseases with autosomal dominant or complex patterns of inheritance.


Assuntos
Variação Genética , Doença de Parkinson/genética , Proteínas Serina-Treonina Quinases/genética , Algoritmos , Sobrevivência Celular , Análise Mutacional de DNA , Exoma , Saúde da Família , Feminino , Dosagem de Genes , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Mutação , Análise de Sequência com Séries de Oligonucleotídeos , Fator 1 de Elongação de Peptídeos/genética , Fenótipo
16.
Mov Disord Clin Pract ; 1(3): 161-172, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30363981

RESUMO

A link between restless legs syndrome (RLS) and iron has been recognized for several decades. Yet, the precise role that iron or other components of iron metabolism play in bringing about RLS is still a matter of debate. During the last few years, many new pieces of evidence from genetics, pathology, imaging, and clinical studies have surfaced. However, the way this evidence fits into the larger picture of RLS as a disease is not always easily understood. To provide a better understanding of the complex interplay between iron metabolism and RLS and highlight areas that need further elucidation, we systematically and critically review the current literature on the role of iron in RLS pathophysiology and treatment with a special emphasis on genetics, neuropathology, cell and animal models, imaging studies, and therapy.

17.
Eur J Hum Genet ; 21(4): 410-4, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22929029

RESUMO

Restless legs syndrome (RLS) is a common multifactorial disease. Some genetic risk factors have been identified. RLS susceptibility also has been related to iron. We therefore asked whether known iron-related genes are candidates for association with RLS and, vice versa, whether known RLS-associated loci influence iron parameters in serum. RLS/control samples (n = 954/1814 in the discovery step, 735/736 in replication 1, and 736/735 in replication 2) were tested for association with SNPs located within 4 Mb intervals surrounding each gene from a list of 111 iron-related genes using a discovery threshold of P = 5 × 10(-4). Two population cohorts (KORA F3 and F4 with together n = 3447) were tested for association of six known RLS loci with iron, ferritin, transferrin, transferrin-saturation, and soluble transferrin receptor. Results were negative. None of the candidate SNPs at the iron-related gene loci was confirmed significantly. An intronic SNP, rs2576036, of KATNAL2 at 18q21.1 was significant in the first (P = 0.00085) but not in the second replication step (joint nominal P-value = 0.044). Especially, rs1800652 (C282Y) in the HFE gene did not associate with RLS. Moreover, SNPs at the known RLS loci did not significantly affect serum iron parameters in the KORA cohorts. In conclusion, the correlation between RLS and iron parameters in serum may be weaker than assumed. Moreover, in a general power analysis, we show that genetic effects are diluted if they are transmitted via an intermediate trait to an end-phenotype. Sample size formulas are provided for small effect sizes.


Assuntos
Ferritinas/genética , Ferro/sangue , Receptores da Transferrina/genética , Síndrome das Pernas Inquietas/genética , Transferrina/genética , Adenosina Trifosfatases/genética , Estudos de Casos e Controles , Estudos de Associação Genética , Proteína da Hemocromatose , Antígenos de Histocompatibilidade Classe I/genética , Proteínas de Homeodomínio/genética , Humanos , Katanina , Proteínas de Membrana/genética , Proteína Meis1 , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único
18.
Hum Mol Genet ; 21(10): 2205-10, 2012 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-22328086

RESUMO

Autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN) is characterized by late onset (30-40 years old) cerebellar ataxia, sensory neuronal deafness, narcolepsy-cataplexy and dementia. We performed exome sequencing in five individuals from three ADCA-DN kindreds and identified DNMT1 as the only gene with mutations found in all five affected individuals. Sanger sequencing confirmed the de novo mutation p.Ala570Val in one family, and showed co-segregation of p.Val606Phe and p.Ala570Val, with the ADCA-DN phenotype, in two other kindreds. An additional ADCA-DN kindred with a p.GLY605Ala mutation was subsequently identified. Narcolepsy and deafness were the first symptoms to appear in all pedigrees, followed by ataxia. DNMT1 is a widely expressed DNA methyltransferase maintaining methylation patterns in development, and mediating transcriptional repression by direct binding to HDAC2. It is also highly expressed in immune cells and required for the differentiation of CD4+ into T regulatory cells. Mutations in exon 20 of this gene were recently reported to cause hereditary sensory neuropathy with dementia and hearing loss (HSAN1). Our mutations are all located in exon 21 and in very close spatial proximity, suggesting distinct phenotypes depending on mutation location within this gene.


Assuntos
Ataxia Cerebelar/genética , DNA (Citosina-5-)-Metiltransferases/genética , Surdez/genética , Genes Dominantes , Mutação , Narcolepsia/genética , Sequência de Aminoácidos , DNA (Citosina-5-)-Metiltransferase 1 , Exoma , Éxons , Humanos , Dados de Sequência Molecular , Linhagem , Fenótipo
19.
BMC Neurol ; 11: 134, 2011 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-22032306

RESUMO

BACKGROUND: Action myoclonus-renal failure syndrome is a hereditary form of progressive myoclonus epilepsy associated with renal failure. It is considered to be an autosomal-recessive disease related to loss-of-function mutations in SCARB2. We studied a German AMRF family, additionally showing signs of demyelinating polyneuropathy and dilated cardiomyopathy. To test the hypothesis whether isolated appearance of individual AMRF syndrome features could be related to heterozygote SCARB2 mutations, we screened for SCARB2 mutations in unrelated patients showing isolated AMRF features. METHODS: In the AMRF family all exons of SCARB2 were analyzed by Sanger sequencing. The mutation screening of unrelated patients with isolated AMRF features affected by either epilepsy (n = 103, progressive myoclonus epilepsy or generalized epilepsy), demyelinating polyneuropathy (n = 103), renal failure (n = 192) or dilated cardiomyopathy (n = 85) was performed as high resolution melting curve analysis of the SCARB2 exons. RESULTS: A novel homozygous 1 bp deletion (c.111delC) in SCARB2 was found by sequencing three affected homozygous siblings of the affected family. A heterozygous sister showed generalized seizures and reduction of nerve conduction velocity in her legs. No mutations were found in the epilepsy, renal failure or dilated cardiomyopathy samples. In the polyneuropathy sample two individuals with demyelinating disease were found to be carriers of a SCARB2 frameshift mutation (c.666delCCTTA). CONCLUSIONS: Our findings indicate that demyelinating polyneuropathy and dilated cardiomyopathy are part of the action myoclonus-renal failure syndrome. Moreover, they raise the possibility that in rare cases heterozygous SCARB2 mutations may be associated with PNP features.


Assuntos
Cardiomiopatias/genética , Doenças Desmielinizantes/genética , Glicoproteínas de Membrana Associadas ao Lisossomo/genética , Mutação , Epilepsias Mioclônicas Progressivas/genética , Receptores Depuradores/genética , Adulto , Sequência de Bases , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Dados de Sequência Molecular , Epilepsias Mioclônicas Progressivas/complicações , Epilepsias Mioclônicas Progressivas/fisiopatologia , Linhagem , Fenótipo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Adulto Jovem
20.
PLoS Genet ; 7(7): e1002171, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21779176

RESUMO

Restless legs syndrome (RLS) is a sensorimotor disorder with an age-dependent prevalence of up to 10% in the general population above 65 years of age. Affected individuals suffer from uncomfortable sensations and an urge to move in the lower limbs that occurs mainly in resting situations during the evening or at night. Moving the legs or walking leads to an improvement of symptoms. Concomitantly, patients report sleep disturbances with consequences such as reduced daytime functioning. We conducted a genome-wide association study (GWA) for RLS in 922 cases and 1,526 controls (using 301,406 SNPs) followed by a replication of 76 candidate SNPs in 3,935 cases and 5,754 controls, all of European ancestry. Herein, we identified six RLS susceptibility loci of genome-wide significance, two of them novel: an intergenic region on chromosome 2p14 (rs6747972, P = 9.03 × 10(-11), OR = 1.23) and a locus on 16q12.1 (rs3104767, P = 9.4 × 10(-19), OR = 1.35) in a linkage disequilibrium block of 140 kb containing the 5'-end of TOX3 and the adjacent non-coding RNA BC034767.


Assuntos
Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 2/genética , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Síndrome das Pernas Inquietas/genética , Humanos , Polimorfismo de Nucleotídeo Único/genética , Reprodutibilidade dos Testes , Fatores de Risco
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