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1.
Brain ; 140(11): 2797-2805, 2017 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-29053787

RESUMEN

Mutations in FUS are causative for amyotrophic lateral sclerosis with a dominant mode of inheritance. In trying to model FUS-amyotrophic lateral sclerosis (ALS) in mouse it is clear that FUS is dosage-sensitive and effects arise from overexpression per se in transgenic strains. Novel models are required that maintain physiological levels of FUS expression and that recapitulate the human disease-with progressive loss of motor neurons in heterozygous animals. Here, we describe a new humanized FUS-ALS mouse with a frameshift mutation, which fulfils both criteria: the FUS Delta14 mouse. Heterozygous animals express mutant humanized FUS protein at physiological levels and have adult onset progressive motor neuron loss and denervation of neuromuscular junctions. Additionally, we generated a novel antibody to the unique human frameshift peptide epitope, allowing specific identification of mutant FUS only. Using our new FUSDelta14 ALS mouse-antibody system we show that neurodegeneration occurs in the absence of FUS protein aggregation. FUS mislocalization increases as disease progresses, and mutant FUS accumulates at the rough endoplasmic reticulum. Further, transcriptomic analyses show progressive changes in ribosomal protein levels and mitochondrial function as early disease stages are initiated. Thus, our new physiological mouse model has provided novel insight into the early pathogenesis of FUS-ALS.


Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Modelos Animales de Enfermedad , Mutación del Sistema de Lectura , Ratones , Agregación Patológica de Proteínas/genética , Proteína FUS de Unión a ARN/genética , Esclerosis Amiotrófica Lateral/metabolismo , Animales , Retículo Endoplásmico Rugoso/metabolismo , Dosificación de Gen , Perfilación de la Expresión Génica , Técnicas de Sustitución del Gen , Heterocigoto , Humanos , Mitocondrias/metabolismo , Neuronas Motoras/metabolismo , Unión Neuromuscular/metabolismo , Agregación Patológica de Proteínas/metabolismo , Proteína FUS de Unión a ARN/metabolismo , Proteínas Ribosómicas/genética
2.
PLoS One ; 4(4): e5003, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-19347040

RESUMEN

WNK1--a serine/threonine kinase involved in electrolyte homeostasis and blood pressure (BP) control--is an excellent candidate gene for essential hypertension (EH). We and others have previously reported association between WNK1 and BP variation. Using tag SNPs (tSNPs) that capture 100% of common WNK1 variation in HapMap, we aimed to replicate our findings with BP and to test for association with phenotypes relating to WNK1 function in the British Genetics of Hypertension (BRIGHT) study case-control resource (1700 hypertensive cases and 1700 normotensive controls). We found multiple variants to be associated with systolic blood pressure, SBP (7/28 tSNPs min-p = 0.0005), diastolic blood pressure, DBP (7/28 tSNPs min-p = 0.002) and 24 hour urinary potassium excretion (10/28 tSNPs min-p = 0.0004). Associations with SBP and urine potassium remained significant after correction for multiple testing (p = 0.02 and p = 0.01 respectively). The major allele (A) of rs765250, located in intron 1, demonstrated the strongest evidence for association with SBP, effect size 3.14 mmHg (95%CI:1.23-4.9), DBP 1.9 mmHg (95%CI:0.7-3.2) and hypertension, odds ratio (OR: 1.3 [95%CI: 1.0-1.7]).We genotyped this variant in six independent populations (n = 14,451) and replicated the association between rs765250 and SBP in a meta-analysis (p = 7 x 10(-3), combined with BRIGHT data-set p = 2 x 10(-4), n = 17,851). The associations of WNK1 with DBP and EH were not confirmed. Haplotype analysis revealed striking associations with hypertension and BP variation (global permutation p<10(-7)). We identified several common haplotypes to be associated with increased BP and multiple low frequency haplotypes significantly associated with lower BP (>10 mmHg reduction) and risk for hypertension (OR<0.60). Our data indicates that multiple rare and common WNK1 variants contribute to BP variation and hypertension, and provide compelling evidence to initiate further genetic and functional studies to explore the role of WNK1 in BP regulation and EH.


Asunto(s)
Presión Sanguínea/genética , Polimorfismo de Nucleótido Simple , Potasio/orina , Proteínas Serina-Treonina Quinasas/genética , Adulto , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Humanos , Péptidos y Proteínas de Señalización Intracelular , Masculino , Persona de Mediana Edad , Antígenos de Histocompatibilidad Menor , Proteína Quinasa Deficiente en Lisina WNK 1
3.
J Infect Dis ; 197(8): 1171-84, 2008 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-18462164

RESUMEN

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a multisystem disease, the pathogenesis of which remains undetermined. We set out to determine the precise abnormalities of gene expression in the blood of patients with CFS/ME. We analyzed gene expression in peripheral blood from 25 patients with CFS/ME diagnosed according to the Centers for Disease Control and Prevention diagnostic criteria and 50 healthy blood donors, using a microarray with a cutoff fold difference of expression of >or=2.5. Genes showing differential expression were further analyzed in 55 patients with CFS/ME and 75 healthy blood donors, using quantitative polymerase chain reaction. Differential expression was confirmed for 88 genes; 85 were upregulated, and 3 were downregulated. Highly represented functions were hematological disease and function, immunological disease and function, cancer, cell death, immune response, and infection. Clustering of quantitative polymerase chain reaction data from patients with CFS/ME revealed 7 subtypes with distinct differences in Medical Outcomes Survey Short Form-36 scores, clinical phenotypes, and severity.


Asunto(s)
Síndrome de Fatiga Crónica/genética , Adulto , Análisis por Conglomerados , Síndrome de Fatiga Crónica/sangre , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Masculino , Familia de Multigenes , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Reacción en Cadena de la Polimerasa , Regiones Promotoras Genéticas , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Factores de Transcripción/genética
4.
J Med Genet ; 44(9): 603-5, 2007 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-17557929

RESUMEN

BACKGROUND: Inositol polyphosphate phosphatase-like 1 (INPPL1, SHIP2) is a negative regulator of insulin signalling and has previously been found to be associated with hypertension, obesity and type 2 diabetes in a cohort of families with diabetes in the UK presenting features of metabolic syndrome. In particular, a haplotype of three genetic polymorphisms (rs2276047, rs9886 and an insertion/deletion polymorphism in intron 1) was found to be strongly associated with increased susceptibility to hypertension. OBJECTIVE AND METHODS: To assess if INPPL1 variants play a direct role in the development of essential hypertension, we genotyped the three previously associated INPPL1 polymorphisms in a cohort of 712 families with severe hypertension from the BRIGHT study transmission disequilibrium test cohort. RESULTS: We found no evidence of significant association between hypertension and any of the three INPPL1 polymorphisms or haplotypes (p>0.1). CONCLUSION: These results suggest that INPPL1 variants may be involved in mechanisms causing hypertension in metabolic syndrome patients specifically.


Asunto(s)
Hipertensión/genética , Síndrome Metabólico/complicaciones , Monoéster Fosfórico Hidrolasas/genética , Polimorfismo de Nucleótido Simple , Adulto , Estudios de Cohortes , Femenino , Haplotipos/genética , Humanos , Hipertensión/etiología , Resistencia a la Insulina/genética , Desequilibrio de Ligamiento , Masculino , Síndrome Metabólico/epidemiología , Síndrome Metabólico/fisiopatología , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatasas , Eliminación de Secuencia , Reino Unido/epidemiología
5.
Am J Hum Genet ; 79(2): 323-31, 2006 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-16826522

RESUMEN

Identification of the genetic influences on human essential hypertension and other complex diseases has proved difficult, partly because of genetic heterogeneity. In many complex-trait resources, additional phenotypic data have been collected, allowing comorbid intermediary phenotypes to be used to characterize more genetically homogeneous subsets. The traditional approach to analyzing covariate-defined subsets has typically depended on researchers' previous expectations for definition of a comorbid subset and leads to smaller data sets, with a concomitant attrition in power. An alternative is to test for dependence between genetic sharing and covariates across the entire data set. This approach offers the advantage of exploiting the full data set and could be widely applied to complex-trait genome scans. However, existing maximum-likelihood methods can be prohibitively computationally expensive, especially since permutation is often required to determine significance. We developed a less computationally intensive score test and applied it to biometric and biochemical covariate data, from 2,044 sibling pairs with severe hypertension, collected by the British Genetics of Hypertension (BRIGHT) study. We found genomewide-significant evidence for linkage with hypertension and several related covariates. The strongest signals were with leaner-body-mass measures on chromosome 20q (maximum LOD = 4.24) and with parameters of renal function on chromosome 5p (maximum LOD = 3.71). After correction for the multiple traits and genetic locations studied, our global genomewide P value was .046. This is the first identity-by-descent regression analysis of hypertension to our knowledge, and it demonstrates the value of this approach for the incorporation of additional phenotypic information in genetic studies of complex traits.


Asunto(s)
Ligamiento Genético , Predisposición Genética a la Enfermedad , Hipertensión/genética , Fenotipo , Mapeo Cromosómico , Femenino , Marcadores Genéticos , Genoma Humano , Humanos , Hipertensión/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Reino Unido
6.
Hypertension ; 48(1): 105-11, 2006 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-16754790

RESUMEN

Human hypertension arises from a combination of genetic factors and lifestyle influences. With cardiovascular disease set to become the number 1 cause of death worldwide, it is important to understand the etiologic mechanisms for hypertension, because these might provide new routes to improved treatment. The British Genetics of Hypertension Study has recently published a primary genome screen that identified 4 chromosomal regions of interest. We have now genotyped additional markers to confirm the most promising regions for follow-up studies. Thirty-four additional microsatellites were genotyped in our severely hypertensive affected sibling pair resource (now 1635 families with 2142 affected sibling pairs), leading to a substantial increase in information content in the regions of interest. We found increased support for linkage of chromosome 5q13 to human hypertension (multipoint logarithm of odds=2.50) with 3 adjacent markers yielding single point logarithm of odds scores of 3.22, 2.84, and 2.51. The placement of additional markers on 2q, 6q, and 9q diminished support for linkage in these regions. However, the addition of new data and families identified novel regions of interest on chromosomes 1q and 11q. The 3 positive markers in the chromosome 5 region were also genotyped in 712 distinct parent-offspring trios with the same severe phenotype to replicate linkage and association. Borderline support for replication was found (P=0.07). We found increased evidence for linkage and borderline-significant evidence for association for a hypertension susceptibility locus on chromosome 5q13 that is worthy of detailed fine mapping and assessment of candidate genes.


Asunto(s)
Cromosomas Humanos Par 5 , Hipertensión/genética , Escala de Lod , Mapeo Cromosómico , Ligamiento Genético , Genotipo , Humanos , Desequilibrio de Ligamiento , Repeticiones de Microsatélite , Hermanos , Reino Unido
7.
Gynecol Oncol ; 103(2): 642-8, 2006 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-16806440

RESUMEN

OBJECTIVES: Previous studies have identified loss of chromosomal regions 7p12-q11.2 and 8p12-p21 in choriocarcinoma suggesting that suppressor genes involved in tumour development may be located within these regions. Our objectives were to refine the regions of loss and evaluate these deletions as prognostic indicators of trophoblastic tumour development following molar pregnancy. METHODS: Fluorescent microsatellite genotyping was used to perform deletion mapping in a series of thirty-nine gestational trophoblastic tumours (GTT) including both choriocarcinoma and placental site trophoblastic tumours. RESULTS: Significant loss of heterozygosity (LOH) was found for both regions in GTT that originated in non-molar pregnancies. Although no common interval of loss was found in those GTT with LOH for the 7q11.2 region, for the 8p12-p21 locus, markers D8S1731 and NEFL defined a minimal region of loss in all tumours showing LOH. However, complete LOH of either region occurred in only a minority of tumours (20%; chromosome 7: 24%; chromosome 8) suggesting that loss of neither region is likely to be a primary event in the development of GTT. This was further supported by the observation that no deletions were found in either region for the fourteen GTT that followed complete molar pregnancies. CONCLUSIONS: While we have defined a minimal interval in 8p12-p21 in which tumour suppressor genes involved in GTT are likely to be located, the data suggest that deletions in 7q11.2 or 8p12-p21 are unlikely to be useful prognostic indicators in the management of patients with molar pregnancies.


Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 7/genética , Cromosomas Humanos Par 8/genética , Enfermedad Trofoblástica Gestacional/genética , Mola Hidatiforme/genética , Neoplasias Uterinas/genética , Adulto , Coriocarcinoma/genética , Coriocarcinoma/patología , Mapeo Cromosómico , Femenino , Enfermedad Trofoblástica Gestacional/patología , Humanos , Mola Hidatiforme/patología , Persona de Mediana Edad , Embarazo , Neoplasias Uterinas/patología
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