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1.
Nature ; 504(7480): 432-6, 2013 Dec 19.
Artículo en Inglés | MEDLINE | ID: mdl-24213632

RESUMEN

Myocardial infarction, a leading cause of death in the Western world, usually occurs when the fibrous cap overlying an atherosclerotic plaque in a coronary artery ruptures. The resulting exposure of blood to the atherosclerotic material then triggers thrombus formation, which occludes the artery. The importance of genetic predisposition to coronary artery disease and myocardial infarction is best documented by the predictive value of a positive family history. Next-generation sequencing in families with several affected individuals has revolutionized mutation identification. Here we report the segregation of two private, heterozygous mutations in two functionally related genes, GUCY1A3 (p.Leu163Phefs*24) and CCT7 (p.Ser525Leu), in an extended myocardial infarction family. GUCY1A3 encodes the α1 subunit of soluble guanylyl cyclase (α1-sGC), and CCT7 encodes CCTη, a member of the tailless complex polypeptide 1 ring complex, which, among other functions, stabilizes soluble guanylyl cyclase. After stimulation with nitric oxide, soluble guanylyl cyclase generates cGMP, which induces vasodilation and inhibits platelet activation. We demonstrate in vitro that mutations in both GUCY1A3 and CCT7 severely reduce α1-sGC as well as ß1-sGC protein content, and impair soluble guanylyl cyclase activity. Moreover, platelets from digenic mutation carriers contained less soluble guanylyl cyclase protein and consequently displayed reduced nitric-oxide-induced cGMP formation. Mice deficient in α1-sGC protein displayed accelerated thrombus formation in the microcirculation after local trauma. Starting with a severely affected family, we have identified a link between impaired soluble-guanylyl-cyclase-dependent nitric oxide signalling and myocardial infarction risk, possibly through accelerated thrombus formation. Reversing this defect may provide a new therapeutic target for reducing the risk of myocardial infarction.


Asunto(s)
Susceptibilidad a Enfermedades/metabolismo , Infarto del Miocardio/metabolismo , Óxido Nítrico/metabolismo , Transducción de Señal , Animales , Chaperonina con TCP-1/genética , Chaperonina con TCP-1/metabolismo , GMP Cíclico/metabolismo , Exoma/genética , Femenino , Predisposición Genética a la Enfermedad , Guanilato Ciclasa/deficiencia , Guanilato Ciclasa/genética , Guanilato Ciclasa/metabolismo , Células HEK293 , Humanos , Masculino , Ratones , Mutación/genética , Infarto del Miocardio/genética , Infarto del Miocardio/fisiopatología , Linaje , Activación Plaquetaria , Receptores Citoplasmáticos y Nucleares/deficiencia , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/metabolismo , Reproducibilidad de los Resultados , Solubilidad , Guanilil Ciclasa Soluble , Trombosis/metabolismo , Vasodilatación
3.
Arterioscler Thromb Vasc Biol ; 35(10): 2207-17, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26293461

RESUMEN

OBJECTIVE: Genome-wide association studies have to date identified 159 significant and suggestive loci for coronary artery disease (CAD). We now report comprehensive bioinformatics analyses of sequence variation in these loci to predict candidate causal genes. APPROACH AND RESULTS: All annotated genes in the loci were evaluated with respect to protein-coding single-nucleotide polymorphism and gene expression parameters. The latter included expression quantitative trait loci, tissue specificity, and miRNA binding. High priority candidate genes were further identified based on literature searches and our experimental data. We conclude that the great majority of causal variations affecting CAD risk occur in noncoding regions, with 41% affecting gene expression robustly versus 6% leading to amino acid changes. Many of these genes differed from the traditionally annotated genes, which was usually based on proximity to the lead single-nucleotide polymorphism. Indeed, we obtained evidence that genetic variants at CAD loci affect 98 genes which had not been linked to CAD previously. CONCLUSIONS: Our results substantially revise the list of likely candidates for CAD and suggest that genome-wide association studies efforts in other diseases may benefit from similar bioinformatics analyses.


Asunto(s)
Enfermedad de la Arteria Coronaria/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Enfermedad de la Arteria Coronaria/fisiopatología , Femenino , Sitios Genéticos , Variación Genética , Humanos , Masculino , MicroARNs/genética , Valor Predictivo de las Pruebas , Regiones Promotoras Genéticas/genética
4.
Hum Mutat ; 36(1): 26-9, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25196272

RESUMEN

Cornelia de Lange syndrome (CdLS) is a well-characterized developmental disorder. The genetic cause of CdLS is a mutation in one of five associated genes (NIPBL, SMC1A, SMC3, RAD21, and HDAC8) accounting for about 70% of cases. To improve our current molecular diagnostic and to analyze some of CdLS candidate genes, we developed and established a gene panel approach. Because recent data indicate a high frequency of mosaic NIPBL mutations that were not detected by conventional sequencing approaches of blood DNA, we started to collect buccal mucosa (BM) samples of our patients that were negative for mutations in the known CdLS genes. Here, we report the identification of three mosaic NIPBL mutations by our high-coverage gene panel sequencing approach that were undetected by classical Sanger sequencing analysis of BM DNA. All mutations were confirmed by the use of highly sensitive SNaPshot fragment analysis using DNA from BM, urine, and fibroblast samples. In blood samples, we could not detect the respective mutation. Finally, in fibroblast samples from all three patients, Sanger sequencing could identify all the mutations. Thus, our study highlights the need for highly sensitive technologies in molecular diagnostic of CdLS to improve genetic diagnosis and counseling of patients and their families.


Asunto(s)
Síndrome de Cornelia de Lange/diagnóstico , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Mutación , Proteínas/genética , Análisis de Secuencia de ADN/métodos , Proteínas de Ciclo Celular , Niño , Preescolar , Síndrome de Cornelia de Lange/genética , Femenino , Predisposición Genética a la Enfermedad , Humanos , Adulto Joven
6.
BMC Cardiovasc Disord ; 14: 108, 2014 Aug 26.
Artículo en Inglés | MEDLINE | ID: mdl-25154303

RESUMEN

BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal-dominant disease leading to markedly elevated low-density lipoprotein (LDL) cholesterol levels and increased risk for premature myocardial infarction (MI). Mutation carriers display variable LDL cholesterol levels, which may obscure the diagnosis. We examined by whole-exome sequencing a family in which multiple myocardial infarctions occurred at a young age with unclear etiology. METHODS: Whole-exome sequencing of three affected family members, validation of the identified variant with Sanger-sequencing, and subsequent co-segregation analysis in the family. RESULTS: The index patient (LDL cholesterol 188 mg/dL) was referred for molecular-genetic investigations. He had coronary artery bypass graft (CABG) at the age of 59 years; 12 out of 15 1st, 2nd and 3rd degree relatives were affected with coronary artery disease (CAD) and/or premature myocardial infarction (MI). We sequenced the whole-exome of the patient and two cousins with premature MI. After filtering, we were left with a potentially disease causing variant in the LDL receptor (LDLR) gene, which we validated by Sanger-sequencing (nucleotide substitution in the acceptor splice-site of exon 10, c.1359-1G > A). Sequencing of all family members available for genetic analysis revealed co-segregation of the variant with CAD (LOD 3.0) and increased LDLC (>190 mg/dL), following correction for statin treatment (LOD 4.3). Interestingly, mutation carriers presented with highly variable corrected (183-354 mg/dL) and on-treatment LDL levels (116-274 mg/dL) such that the diagnosis of FH in this family was made only after the molecular-genetic analysis. CONCLUSION: Even in families with unusual clustering of CAD FH remains to be underdiagnosed, which underscores the need for implementation of systematic screening programs. Whole-exome sequencing may facilitate identification of disease-causing variants in families with unclear etiology of MI and enable preventive treatment of mutation carriers in a more timely fashion.


Asunto(s)
Exoma , Pruebas Genéticas/métodos , Hiperlipoproteinemia Tipo II/genética , Mutación , Infarto del Miocardio/genética , Receptores de LDL/genética , Adulto , Edad de Inicio , Anciano , Biomarcadores/sangre , LDL-Colesterol/sangre , Puente de Arteria Coronaria , Análisis Mutacional de ADN , Femenino , Predisposición Genética a la Enfermedad , Humanos , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/epidemiología , Masculino , Persona de Mediana Edad , Infarto del Miocardio/sangre , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/epidemiología , Infarto del Miocardio/cirugía , Linaje , Fenotipo , Valor Predictivo de las Pruebas
9.
Sci Rep ; 11(1): 22651, 2021 11 22.
Artículo en Inglés | MEDLINE | ID: mdl-34811390

RESUMEN

Significant progress has been made in elucidating genetic risk factors influencing Type 1 diabetes (T1D); however, features other than genetic variants that initiate and/or accelerate islet autoimmunity that lead to the development of clinical T1D remain largely unknown. We hypothesized that genetic and environmental risk factors can both contribute to T1D through dynamic alterations of molecular interactions in physiologic networks. To test this hypothesis, we utilized longitudinal blood transcriptomic profiles in The Environmental Determinants of Diabetes in the Young (TEDDY) study to generate gene co-expression networks. In network modules that contain immune response genes associated with T1D, we observed highly dynamic differences in module connectivity in the 600 days (~ 2 years) preceding clinical diagnosis of T1D. Our results suggest that gene co-expression is highly plastic and that connectivity differences in T1D-associated immune system genes influence the timing and development of clinical disease.


Asunto(s)
Diabetes Mellitus Tipo 1/genética , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Redes Reguladoras de Genes , Estudios de Casos y Controles , Niño , Preescolar , Biología Computacional , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Modelos Estadísticos , Estudios Prospectivos , Biología de Sistemas , Transcriptoma
10.
N Engl J Med ; 357(5): 443-53, 2007 Aug 02.
Artículo en Inglés | MEDLINE | ID: mdl-17634449

RESUMEN

BACKGROUND: Modern genotyping platforms permit a systematic search for inherited components of complex diseases. We performed a joint analysis of two genomewide association studies of coronary artery disease. METHODS: We first identified chromosomal loci that were strongly associated with coronary artery disease in the Wellcome Trust Case Control Consortium (WTCCC) study (which involved 1926 case subjects with coronary artery disease and 2938 controls) and looked for replication in the German MI [Myocardial Infarction] Family Study (which involved 875 case subjects with myocardial infarction and 1644 controls). Data on other single-nucleotide polymorphisms (SNPs) that were significantly associated with coronary artery disease in either study (P<0.001) were then combined to identify additional loci with a high probability of true association. Genotyping in both studies was performed with the use of the GeneChip Human Mapping 500K Array Set (Affymetrix). RESULTS: Of thousands of chromosomal loci studied, the same locus had the strongest association with coronary artery disease in both the WTCCC and the German studies: chromosome 9p21.3 (SNP, rs1333049) (P=1.80x10(-14) and P=3.40x10(-6), respectively). Overall, the WTCCC study revealed nine loci that were strongly associated with coronary artery disease (P<1.2x10(-5) and less than a 50% chance of being falsely positive). In addition to chromosome 9p21.3, two of these loci were successfully replicated (adjusted P<0.05) in the German study: chromosome 6q25.1 (rs6922269) and chromosome 2q36.3 (rs2943634). The combined analysis of the two studies identified four additional loci significantly associated with coronary artery disease (P<1.3x10(-6)) and a high probability (>80%) of a true association: chromosomes 1p13.3 (rs599839), 1q41 (rs17465637), 10q11.21 (rs501120), and 15q22.33 (rs17228212). CONCLUSIONS: We identified several genetic loci that, individually and in aggregate, substantially affect the risk of development of coronary artery disease.


Asunto(s)
Cromosomas Humanos Par 9/genética , Enfermedad de la Arteria Coronaria/genética , Infarto del Miocardio/genética , Polimorfismo de Nucleótido Simple , Cromosomas Humanos Par 2/genética , Cromosomas Humanos Par 6/genética , Femenino , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Genoma Humano , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Riesgo
11.
J Bone Miner Res ; 35(9): 1751-1764, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32311160

RESUMEN

Mechanical loading is a potent strategy to induce bone formation, but with aging, the bone formation response to the same mechanical stimulus diminishes. Our main objectives were to (i) discover the potential transcriptional differences and (ii) compare the periosteal cell proliferation between tibias of young-adult and old mice in response to strain-matched mechanical loading. First, to discover potential age-related transcriptional differences, we performed RNA sequencing (RNA-seq) to compare the loading responses between tibias of young-adult (5-month) and old (22-month) C57BL/6N female mice following 1, 3, or 5 days of axial loading (loaded versus non-loaded). Compared to young-adult mice, old mice had less transcriptional activation following loading at each time point, as measured by the number of differentially expressed genes (DEGs) and the fold-changes of the DEGs. Old mice engaged fewer pathways and gene ontology (GO) processes, showing less activation of processes related to proliferation and differentiation. In tibias of young-adult mice, we observed prominent Wnt signaling, extracellular matrix (ECM), and neuronal responses, which were diminished with aging. Additionally, we identified several targets that may be effective in restoring the mechanoresponsiveness of aged bone, including nerve growth factor (NGF), Notum, prostaglandin signaling, Nell-1, and the AP-1 family. Second, to directly test the extent to which periosteal cell proliferation was diminished in old mice, we used bromodeoxyuridine (BrdU) in a separate cohort of mice to label cells that divided during the 5-day loading interval. Young-adult and old mice had an average of 15.5 and 16.7 BrdU+ surface cells/mm, respectively, suggesting that impaired proliferation in the first 5 days of loading does not explain the diminished bone formation response with aging. We conclude that old mice have diminished transcriptional activation following mechanical loading, but periosteal proliferation in the first 5 days of loading does not differ between tibias of young-adult and old mice. © 2020 American Society for Bone and Mineral Research.


Asunto(s)
Tibia , Activación Transcripcional , Animales , Proliferación Celular , Femenino , Ratones , Ratones Endogámicos C57BL , Osteogénesis , Estrés Mecánico , Soporte de Peso
12.
Sci Rep ; 9(1): 2959, 2019 02 27.
Artículo en Inglés | MEDLINE | ID: mdl-30814609

RESUMEN

The genetics of many congenital heart diseases (CHDs) can only unsatisfactorily be explained by known chromosomal or Mendelian syndromes. Here, we present sequencing data of a family with a potentially multigenic origin of CHD. Twelve of nineteen family members carry a familial mutation [NM_004329.2:c.1328 G > A (p.R443H)] which encodes a predicted deleterious variant of BMPR1A. This mutation co-segregates with a linkage region on chromosome 1 that associates with the emergence of severe CHDs including Ebstein's anomaly, atrioventricular septal defect, and others. We show that the continuous overexpression of the zebrafish homologous mutation bmpr1aap.R438H within endocardium causes a reduced AV valve area, a downregulation of Wnt/ß-catenin signalling at the AV canal, and growth of additional tissue mass in adult zebrafish hearts. This finding opens the possibility of testing genetic interactions between BMPR1A and other candidate genes within linkage region 1 which may provide a first step towards unravelling more complex genetic patterns in cardiovascular disease aetiology.


Asunto(s)
Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/genética , Cardiopatías Congénitas/genética , Adulto , Animales , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/metabolismo , Modelos Animales de Enfermedad , Endocardio/metabolismo , Femenino , Ligamiento Genético/genética , Humanos , Masculino , Mutación/genética , Pez Cebra
13.
Circ Genom Precis Med ; 11(8): e001977, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-30354342

RESUMEN

BACKGROUND: Genome-wide association studies have identified multiple loci associated with coronary artery disease and myocardial infarction, but only a few of these loci are current targets for on-market medications. To identify drugs suitable for repurposing and their targets, we created 2 unique pipelines integrating public data on 49 coronary artery disease/myocardial infarction-genome-wide association studies loci, drug-gene interactions, side effects, and chemical interactions. METHODS: We first used publicly available genome-wide association studies results on all phenotypes to predict relevant side effects, identified drug-gene interactions, and prioritized candidates for repurposing among existing drugs. Second, we prioritized gene product targets by calculating a druggability score to estimate how accessible pockets of coronary artery disease/myocardial infarction-associated gene products are, then used again the genome-wide association studies results to predict side effects, excluded loci with widespread cross-tissue expression to avoid housekeeping and genes involved in vital processes and accordingly ranked the remaining gene products. RESULTS: These pipelines ultimately led to 3 suggestions for drug repurposing: pentolinium, adenosine triphosphate, and riociguat (to target CHRNB4, ACSS2, and GUCY1A3, respectively); and 3 proteins for drug development: LMOD1 (leiomodin 1), HIP1 (huntingtin-interacting protein 1), and PPP2R3A (protein phosphatase 2, regulatory subunit b-double prime, α). Most current therapies for coronary artery disease/myocardial infarction treatment were also rediscovered. CONCLUSIONS: Integration of genomic and pharmacological data may prove beneficial for drug repurposing and development, as evidence from our pipelines suggests.


Asunto(s)
Fármacos Cardiovasculares , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Enfermedad de la Arteria Coronaria/genética , Descubrimiento de Drogas/métodos , Reposicionamiento de Medicamentos/métodos , Sitios Genéticos , Terapia Molecular Dirigida/métodos , Algoritmos , Animales , Fármacos Cardiovasculares/farmacocinética , Fármacos Cardiovasculares/uso terapéutico , Evaluación Preclínica de Medicamentos/métodos , Interacciones Farmacológicas/genética , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/genética , Interacción Gen-Ambiente , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Simulación del Acoplamiento Molecular , Pruebas de Farmacogenómica , Polimorfismo de Nucleótido Simple , Factores de Riesgo
14.
Sci Rep ; 8(1): 3434, 2018 02 21.
Artículo en Inglés | MEDLINE | ID: mdl-29467471

RESUMEN

Genome-wide association studies (GWAS) have identified over two hundred chromosomal loci that modulate risk of coronary artery disease (CAD). The genes affected by variants at these loci are largely unknown and an untapped resource to improve our understanding of CAD pathophysiology and identify potential therapeutic targets. Here, we prioritized 68 genes as the most likely causal genes at genome-wide significant loci identified by GWAS of CAD and examined their regulatory roles in 286 metabolic and vascular tissue gene-protein sub-networks ("modules"). The modules and genes within were scored for CAD druggability potential. The scoring enriched for targets of cardiometabolic drugs currently in clinical use and in-depth analysis of the top-scoring modules validated established and revealed novel target tissues, biological processes, and druggable targets. This study provides an unprecedented resource of tissue-defined gene-protein interactions directly affected by genetic variance in CAD risk loci.


Asunto(s)
Enfermedad de la Arteria Coronaria/genética , Redes Reguladoras de Genes , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Descubrimiento de Drogas , Redes Reguladoras de Genes/efectos de los fármacos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Desequilibrio de Ligamiento , Terapia Molecular Dirigida , Polimorfismo de Nucleótido Simple/efectos de los fármacos , Sitios de Carácter Cuantitativo/efectos de los fármacos
15.
PLoS One ; 12(8): e0182999, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28829817

RESUMEN

Glatiramer acetate is used therapeutically in multiple sclerosis but also known for adverse effects including elevated coronary artery disease (CAD) risk. The mechanisms underlying the cardiovascular side effects of the medication are unclear. Here, we made use of the chromosomal variation in the genes that are known to be affected by glatiramer treatment. Focusing on genes and gene products reported by drug-gene interaction database to interact with glatiramer acetate we explored a large meta-analysis on CAD genome-wide association studies aiming firstly, to investigate whether variants in these genes also affect cardiovascular risk and secondly, to identify new CAD risk genes. We traced association signals in a 200-kb region around genomic positions of genes interacting with glatiramer in up to 60 801 CAD cases and 123 504 controls. We validated the identified association in additional 21 934 CAD cases and 76 087 controls. We identified three new CAD risk alleles within the TGFB1 region on chromosome 19 that independently affect CAD risk. The lead SNP rs12459996 was genome-wide significantly associated with CAD in the extended meta-analysis (odds ratio 1.09, p = 1.58×10-12). The other two SNPs at the locus were not in linkage disequilibrium with the lead SNP and by a conditional analysis showed p-values of 4.05 × 10-10 and 2.21 × 10-6. Thus, studying genes reported to interact with glatiramer acetate we identified genetic variants that concordantly with the drug increase the risk of CAD. Of these, TGFB1 displayed signal for association. Indeed, the gene has been associated with CAD previously in both in vivo and in vitro studies. Here we establish genome-wide significant association with CAD in large human samples.


Asunto(s)
Enfermedades Cardiovasculares/genética , Predisposición Genética a la Enfermedad , Acetato de Glatiramer/efectos adversos , Enfermedades Cardiovasculares/inducido químicamente , Estudios de Casos y Controles , Humanos , Desequilibrio de Ligamiento , Polimorfismo de Nucleótido Simple
16.
Sci Rep ; 7(1): 10252, 2017 08 31.
Artículo en Inglés | MEDLINE | ID: mdl-28860667

RESUMEN

Cyclooxygenase-2 inhibitors (coxibs) are characterized by multiple molecular off-target effects and increased coronary artery disease (CAD) risk. Here, we systematically explored common variants of genes representing molecular targets of coxibs for association with CAD. Given a broad spectrum of pleiotropic effects of coxibs, our intention was to narrow potential mechanisms affecting CAD risk as we hypothesized that the affected genes may also display genomic signals of coronary disease risk. A Drug Gene Interaction Database search identified 47 gene products to be affected by coxibs. We traced association signals in 200-kb regions surrounding these genes in 84,813 CAD cases and 202,543 controls. Based on a threshold of 1 × 10-5 (Bonferroni correction for 3131 haplotype blocks), four gene loci yielded significant associations. The lead SNPs were rs7270354 (MMP9), rs4888383 (BCAR1), rs6905288 (VEGFA1), and rs556321 (CACNA1E). By additional genotyping, rs7270354 at MMP9 and rs4888383 at BCAR1 also reached the established GWAS threshold for genome-wide significance. The findings demonstrate overlap of genes affected by coxibs and those mediating CAD risk and points to further mechanisms, which are potentially responsible for coxib-associated CAD risk. The novel approach furthermore suggests that genetic studies may be useful to explore the clinical relevance of off-target drug effects.


Asunto(s)
Cardiotoxicidad/etiología , Inhibidores de la Ciclooxigenasa 2/efectos adversos , Farmacogenética , Mapeo Cromosómico , Biología Computacional/métodos , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Bases de Datos Genéticas , Bases de Datos Farmacéuticas , Perfilación de la Expresión Génica , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Farmacogenética/métodos , Polimorfismo de Nucleótido Simple
17.
Genes (Basel) ; 8(10)2017 Oct 18.
Artículo en Inglés | MEDLINE | ID: mdl-29057844

RESUMEN

Mutations in RAB (member of the Ras superfamily) genes are increasingly recognized as cause of a variety of disorders including neurological conditions. While musician's dystonia (MD) and writer's dystonia (WD) are task-specific movement disorders, other dystonias persistently affect postures as in cervical dystonia. Little is known about the underlying etiology. Next-generation sequencing revealed a rare missense variant (c.586A>G; p.Ile196Val) in RAB12 in two of three MD/WD families. Next, we tested 916 additional dystonia patients; 512 Parkinson's disease patients; and 461 healthy controls for RAB12 variants and identified 10 additional carriers of rare missense changes among dystonia patients (1.1%) but only one carrier in non-dystonic individuals (0.1%; p = 0.005). The detected variants among index patients comprised p.Ile196Val (n = 6); p.Ala174Thr (n = 3); p.Gly13Asp; p.Ala148Thr; and p.Arg181Gln in patients with MD; cervical dystonia; or WD. Two relatives of MD patients with WD also carried p.Ile196Val. The two variants identified in MD patients (p.Ile196Val; p.Gly13Asp) were characterized on endogenous levels in patient-derived fibroblasts and in two RAB12-overexpressing cell models. The ability to hydrolyze guanosine triphosphate (GTP), so called GTPase activity, was increased in mutants compared to wildtype. Furthermore, subcellular distribution of RAB12 in mutants was altered in fibroblasts. Soluble Transferrin receptor 1 levels were reduced in the blood of all three tested p.Ile196Val carriers. In conclusion, we demonstrate an enrichment of missense changes among dystonia patients. Functional characterization revealed altered enzyme activity and lysosomal distribution in mutants suggesting a contribution of RAB12 variants to MD and other dystonias.

18.
Eur J Hum Genet ; 24(2): 191-7, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26036859

RESUMEN

Familial hypercholesterolemia (FH) is an oligogenic disorder characterized by markedly elevated low-density lipoprotein cholesterol (LDLC) levels. Variants in four genes have been reported to cause the classical autosomal-dominant form of the disease. FH is largely under-diagnosed in European countries. As FH increases the risk for coronary artery disease (CAD) and myocardial infarction (MI), it might be specifically overlooked in the large number of such patients. Here, we systematically examined the frequency of potential FH-causing variants by exome sequencing in 255 German patients with premature MI and a positive family history for CAD. We further performed co-segregation analyses in an average of 5.5 family members per MI patient. In total, we identified 11 potential disease-causing variants that co-segregate within the families, that is, 5% of patients with premature MI and positive CAD family history had FH. Eight variants were previously reported as disease-causing and three are novel (LDLR.c.811G>A p.(V271I)), PCSK9.c.610G>A (p.(D204N)) and STAP1.c.139A>G (p.(T47A))). Co-segregation analyses identified multiple additional family members carrying one of these FH variants and the clinical phenotype of either FH (n=2) or FH and premature CAD (n=15). However, exome sequencing also revealed that some variants in FH genes, which have been reported to cause FH, do not co-segregate with FH. The data reveal that a large proportion of FH patients escape the diagnosis, even when they have premature MI. Hence, systematic molecular-genetic screening for FH in such patients may reveal a substantial number of cases and thereby allow a timely LDLC-lowering in both FH/MI patients as well as their variant-carrying family members.


Asunto(s)
LDL-Colesterol/genética , Enfermedad de la Arteria Coronaria/genética , Hiperlipoproteinemia Tipo II/genética , Infarto del Miocardio/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Adulto , Anciano , LDL-Colesterol/sangre , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/patología , Europa (Continente) , Exoma/genética , Femenino , Pruebas Genéticas , Humanos , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/patología , Masculino , Persona de Mediana Edad , Mutación , Infarto del Miocardio/sangre , Infarto del Miocardio/patología , Polimorfismo de Nucleótido Simple , Proproteína Convertasa 9 , Proproteína Convertasas/genética , Factores de Riesgo , Serina Endopeptidasas/genética
19.
J Neurol ; 262(1): 187-93, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25359261

RESUMEN

Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal movements or postures. Several genetic causes of dystonia have been elucidated but genetic causes of dystonia specifically affecting females have not yet been described. In the present study, we investigated a large dystonia family from New Zealand in which only females were affected. They presented with a generalized form of the disorder including laryngeal, cervical, and arm dystonia. We found a novel, likely disease-causing, three base-pair deletion (c.443_445delGAG, p.Ser148del) in ATP1A3 in this family by combining genome and exome sequencing. Mutations in ATP1A3 have previously been linked to rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and CAPOS syndrome. Therefore, we re-examined our patients with a specific focus on typical symptoms of these conditions. It turned out that all patients reported a rapid onset of dystonic symptoms following a trigger suggesting a diagnosis of RDP. Notably, none of the patients showed clear symptoms of parkinsonism or symptoms specific for AHC or CAPOS. The ATP1A3 gene is located on chromosome 19q13.2, thus, providing no obvious explanation for the preponderance to affect females. Interestingly, we also identified one unaffected male offspring carrying the p.Ser148del mutation suggesting reduced penetrance of this mutation, a phenomenon that has also been observed for other RDP-causing mutations in ATP1A3. Although phenotypic information in this family was initially incomplete, the identification of the p.Ser148del ATP1A3 mutation elicited clinical re-examination of patients subsequently allowing establishing the correct diagnosis, a phenomenon known as "reverse phenotyping".


Asunto(s)
Trastornos Distónicos/genética , ATPasa Intercambiadora de Sodio-Potasio/genética , Adulto , Anciano , Trastornos Distónicos/fisiopatología , Exoma , Femenino , Humanos , Persona de Mediana Edad , Mutación , Nueva Zelanda , Linaje , Análisis de Secuencia de ADN
20.
Eur J Hum Genet ; 23(10): 1334-40, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25604858

RESUMEN

X-linked recessive dystonia-parkinsonism is a rare movement disorder that is highly prevalent in Panay Island in the Philippines. Earlier studies identified seven different genetic alterations within a 427-kb disease locus on the X chromosome; however, the exact disease-causing variant among these is still not unequivocally determined. To further investigate the genetic cause of this disease, we sequenced all previously reported genetic alterations in 166 patients and 473 Filipino controls. Singly occurring variants in our ethnically matched controls would have allowed us to define these as polymorphisms, but none were found. Instead, we identified five patients carrying none of the disease-associated variants, and one male control carrying all of them. In parallel, we searched for novel single-nucleotide variants using next-generation sequencing. We did not identify any shared variants in coding regions of the X chromosome. However, by validating intergenic variants discovered via genome sequencing, we were able to define the boundaries of the disease-specific haplotype and narrow the disease locus to a 294-kb region that includes four known genes. Using microarray-based analyses, we ruled out the presence of disease-linked copy number variants within the implicated region. Finally, we utilized in silico analysis and detected no strong evidence of regulatory regions surrounding the disease-associated variants. In conclusion, our finding of disease-specific variants occurring in complete linkage disequilibrium raises new insights and intriguing questions about the origin of the disease haplotype, the existence of phenocopies and of reduced penetrance, and the causative genetic alteration in XDP.


Asunto(s)
Cromosomas Humanos X/genética , Trastornos Distónicos/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Ligamiento Genético/genética , Enfermedad de Parkinson/genética , Adulto , Anciano , Mapeo Cromosómico/métodos , Haplotipos/genética , Humanos , Desequilibrio de Ligamiento/genética , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Filipinas , Polimorfismo Genético/genética
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