RESUMEN
Hermansky-Pudlak syndrome (HPS) is a disorder of organelle biogenesis in which oculocutaneous albinism, bleeding and pulmonary fibrosis result from defects of melanosomes, platelet dense granules and lysosomes. HPS is common in Puerto Rico, where it is caused by mutations in the genes HPS1 and, less often, HPS3 (ref. 8). In contrast, only half of non-Puerto Rican individuals with HPS have mutations in HPS1 (ref. 9), and very few in HPS3 (ref. 10). In the mouse, more than 15 loci manifest mutant phenotypes similar to human HPS, including pale ear (ep), the mouse homolog of HPS1 (refs 13,14). Mouse ep has a phenotype identical to another mutant, light ear (le), which suggests that the human homolog of le is a possible human HPS locus. We have identified and found mutations of the human le homolog, HPS4, in a number of non-Puerto Rican individuals with HPS, establishing HPS4 as an important HPS locus in humans. In addition to their identical phenotypes, le and ep mutant mice have identical abnormalities of melanosomes, and in transfected melanoma cells the HPS4 and HPS1 proteins partially co-localize in vesicles of the cell body. In addition, the HPS1 protein is absent in tissues of le mutant mice. These results suggest that the HPS4 and HPS1 proteins may function in the same pathway of organelle biogenesis.
Asunto(s)
Síndrome de Hermanski-Pudlak/genética , Mutación , Proteínas/genética , Secuencia de Aminoácidos , Animales , Northern Blotting , Técnica del Anticuerpo Fluorescente , Factores de Intercambio de Guanina Nucleótido , Homocigoto , Humanos , Ratones , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Proteínas/química , Homología de Secuencia de AminoácidoRESUMEN
Every year, about 60â000 people in Germany contract colo-rectal carcinoma. Hereditary factors are the cause in approx. 5â% and those affected often fall ill at a young age. Often there are concrete indications of an individual high risk in affected families. The identification of persons at risk enables a targeted early detection and prevention of cancer as an important interdisciplinary medical task. The current AWMF guideline "Colorectal carcinoma" makes concrete statements in this regard.
Asunto(s)
Neoplasias Colorrectales , Adolescente , Adulto , Anciano , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/prevención & control , Detección Precoz del Cáncer , Femenino , Predisposición Genética a la Enfermedad , Alemania , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Mutations in either the EXT1 or EXT2 genes lead to Multiple Osteochondromas (MO), an autosomal dominantly inherited disorder. This is a report on clinical findings and results of molecular analyses of both genes in 23 German patients affected by MO. Mutation screening was performed by using denaturing high performance liquid chromatography (dHPLC) and automated sequencing. In 17 of 23 patients novel pathogenic mutations have been identified; eleven in the EXT1 and six in the EXT2 gene. Five patients were carriers of recurrent mutations in the EXT2 gene (p.Asp227Asn, p.Gln172X, p.Gln258X) and one patient had no detectable mutation. To demonstrate their pathogenic effect on transcription, two complex mutations in EXT1 and EXT2 and three splice site mutations were characterized by mRNA investigations. The results obtained provide evidence for different aberrant splice effects - usage of new cryptic splice sites and exon skipping. Our study extends the mutational spectrum and understanding of pathogenic effects of mutations in EXT1 and EXT2.
Asunto(s)
Exostosis Múltiple Hereditaria/genética , Mutación , N-Acetilglucosaminiltransferasas/genética , Población Blanca/genética , Adolescente , Adulto , Secuencia de Bases , Niño , Femenino , Alemania , Humanos , Masculino , Datos de Secuencia Molecular , Empalme del ARN , Adulto JovenRESUMEN
Uncoupling protein 2 (UCP2) is a member of the mitochondrial proton transport family that uncouples proton entry to the mitochondria from ATP synthesis. UCP2 expression levels have been linked to predisposition to diabetes and obesity. In addition, UCP2 prevents neuronal death and injury. Here we show that the common -866G/A promoter polymorphism is associated with susceptibility to multiple sclerosis (MS) in the German population. We analysed altogether 1,097 MS patients and 462 control subjects from two cohorts and found that the common G allele is associated with disease susceptibility (p = 0.0015). The UCP2 -866G allele is correlated with lower levels of UCP2 expression as shown here in vitro and in vivo. Thus, UCP2 promoter polymorphism may contribute to MS susceptibility by regulating the level of UCP2 protein in the central nervous and/or the immune systems.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Proteínas de Transporte de Membrana/genética , Proteínas Mitocondriales/genética , Esclerosis Múltiple/genética , Polimorfismo Genético , Regiones Promotoras Genéticas/genética , Adolescente , Adulto , Alelos , Células Cultivadas , Femenino , Frecuencia de los Genes , Humanos , Canales Iónicos , Masculino , Persona de Mediana Edad , Monocitos/metabolismo , Linfocitos T/metabolismo , Proteína Desacopladora 2RESUMEN
New statistics are developed to gather the contribution of many alleles at different loci to common diseases. Both inferential and descriptive statistics are included in order to uncover epistatic effects as well as heterogeneity. The problem of multiple testing is circumvented by considering a global null hypothesis. Global testing is supplemented by descriptive methods that make use of measures like odds ratio or the P-value of individually tested allele combinations. Visualization helps to reflect complex data sets. The methods described here have been scrutinized by statistical simulations, and we show that power gains can be substantial as compared to single locus statistics. Typing data of multiple sclerosis patients and controls are investigated, representing an example of larger scale information in screening candidate genes for their impact on complex diseases. New insights emerge from this data set demonstrating genetic heterogeneity and evidence for epistasis.
Asunto(s)
Epistasis Genética , Heterogeneidad Genética , Estadística como Asunto , Adulto , Estudios de Casos y Controles , Interpretación Estadística de Datos , Frecuencia de los Genes , Enfermedades Genéticas Congénitas/genética , Humanos , Modelos Genéticos , Modelos Estadísticos , Esclerosis Múltiple/genética , Oportunidad RelativaRESUMEN
BACKGROUND: Since contradictory results have been reported, we reanalysed the 77C-->G transition in exon 4 of the protein-tyrosine phosphatase receptor-type C (PTPRC also known as CD45) in a large cohort of German MS patients and controls. Different isoforms of the protein are expressed, depending on alternative splicing of exons 4 (CD45RA), 5 (CD45RB) and 6 (CD45RC) (CD45RO, exons 4-6 spliced out). The 77C-->G transition does not change the amino acid sequence, but it is probably part of a motif necessary for splicing leading to the isoform CD45RA. The expression of CD45RA is increased in 77C/G heterozygous individuals. The aim of the study was to clarify the importance of the PTPRC 77C-->G transition in our German cohort of MS patients. METHODS: PCR products of exon 4 were digested using endonuclease MspI. The resulting restriction fragments of the wildtype C allele are 198 and 62 bp in length. In the G allele an additional restriction site is present yielding fragments of 114 and 84 bp. RESULTS: The G allele was identified in 10 of the 347 controls (1.4%) and in 7 of 454 MS patients (0.8%; Table 1). No homozygous individuals were found either in the control or in the patient group. Genetic association between the PTPRC 77C-->G transition and MS susceptibility was excluded in the MS cohort. In addition, subgrouping patients according to differences in the clinical course of MS or according to HLA-DRB1*15 status did not yield significant differences. CONCLUSIONS: The 77C-->G transition in exon 4 of the PTPRC gene may contribute to MS susceptibility only in very few families, if at all, but it is not relevant for the majority of MS cases, including virtually all German patients.
RESUMEN
BACKGROUND: Rheumatoid arthritis (RA) and juvenile rheumatoid arthritis (JRA) are complex multifactorial diseases caused by environmental influences and an unknown number of predisposing genes. The present study was undertaken in order to investigate association of polymorphisms in candidate genes with RA and JRA in German subjects. RESULTS: Up to 200 unrelated German RA and JRA patients each and 300-400 healthy controls have been genotyped for HLA-DRB1, TNFa, TNFA -238a/g, TNFA -308a/g, TNFA -857c/t, TNFR1 -609g/t, TNFR1 P12P, TNFR2 del 15bp, IKBL -332a/g, IKBL -132t/a, IKBL C224R, CTLA4 -318c/t, CTLA4 T17A, PTPRC P57P, MIF -173g/c, the MIF and IFNG microsatellites as well as for D17S795, D17S807, D17S1821 by polyacrylamide gel electrophoresis, single-strand conformation polymorphism analysis, restriction fragment length polymorphism analysis or allele specific hybridization. None of the investigated genetic markers is associated with both, RA and JRA, but there are some statistically significant differences between patients and controls that have to be discussed sensibly. CONCLUSIONS: The difficulty in investigating the genetics of complex disorders like RA and JRA may arise from genetic heterogeneity in the clinically defined disease cohorts (and generally limited power of such studies). In addition, several to many genes appear to be involved in the genetic predisposition, each of which exerting only small effects. The number of investigated patients has to be increased to establish the possibility of subdivison of the patients according their clinical symptoms, severity of disease, HLA status and other genetic characteristics.
Asunto(s)
Artritis Juvenil/genética , Artritis Reumatoide/genética , Predisposición Genética a la Enfermedad/genética , Proteínas Adaptadoras Transductoras de Señales , Adulto , Edad de Inicio , Anciano , Alelos , Antígenos CD/genética , Antígenos de Diferenciación/genética , Antígeno CTLA-4 , Niño , ADN/genética , Femenino , Frecuencia de los Genes , Genotipo , Alemania , Antígenos HLA-DR/genética , Cadenas HLA-DRB1 , Antígenos de Histocompatibilidad Clase II/genética , Humanos , Interferón gamma/genética , Antígenos Comunes de Leucocito/genética , Factores Inhibidores de la Migración de Macrófagos/genética , Masculino , Repeticiones de Microsatélite/genética , Persona de Mediana Edad , Polimorfismo Genético , Polimorfismo Conformacional Retorcido-Simple , Receptores del Factor de Necrosis Tumoral/genética , Receptores Tipo I de Factores de Necrosis Tumoral , Receptores Tipo II del Factor de Necrosis Tumoral , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
The genetics of multifactorial diseases characterized by autoimmune phenomena are elusive so far. Yet, it is clear that the genetic contribution to a given clinically defined autoimmune disease entity is mostly variable and highly complex. On the basis of two basically different model diseases, Wegener's Granulomatosis and multiple sclerosis, approaches are discussed to unravel at least certain genetic predisposition factors. Major difficulties in these analyses arise from (in)exact definition of the clinical phenotype (disease entity), the vast number of potential candidate genes, the small to modest contribution of each genetic variation to disease risk and the combinatorial possibilities.
Asunto(s)
Enfermedades Autoinmunes/genética , Granulomatosis con Poliangitis/genética , Granulomatosis con Poliangitis/inmunología , Antígenos de Histocompatibilidad Clase II , Humanos , Herencia Multifactorial , Esclerosis Múltiple/genética , Esclerosis Múltiple/inmunología , Mieloblastina , Serina Endopeptidasas/inmunologíaRESUMEN
Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system with putative autoimmune aetiology and complex genetic background. Here, we report the results of a genome screen for linkage disequilibrium (LD) by using 6000 microsatellite markers in 198 HLA-DRB1*15-positive MS patients and 198 unrelated controls (pooled DNA); 4666 analysed markers could be included in the resulting association map, from which 87 revealed significant differences between MS cases and controls.