RESUMEN
The association of the tumor necrosis factor alpha (TNFalpha) -G308A promoter polymorphism with schizophrenia has complemented clinical findings of increased levels of the TNFalpha cytokine in schizophrenic patients, with some support for a functional consequence of the variant. Our previous studies of genetic causes in schizophrenia supported findings of linkage to the major histocompatibility complex (MHC) region where the TNFalpha gene is located as well as association with the -G308A promoter polymorphism. While the common G-allele shows association in our sample, association with the A-allele has been reported by other groups. This suggests linkage disequilibrium (LD) rather than direct involvement in the disorder. In order to define LD of DNA variants with the disorder in this area, we analyzed 36 SNPs in a 165-kb region around this polymorphism. We detected nominally significant associations (P < 0.05) of three markers (including the -G308A promoter polymorphism) and multiple haplotypes with schizophrenia in our sample of 204 families (79 sib-pairs and 125 trios). The association is largely restricted to a 30 kb high LD region/block and should assist in the identification of a schizophrenia susceptibility gene within the block or elsewhere in the MHC.
Asunto(s)
Desequilibrio de Ligamiento , Polimorfismo de Nucleótido Simple , Esquizofrenia/genética , Factor de Necrosis Tumoral alfa/genética , Familia , Frecuencia de los Genes , Genes MHC Clase I , Marcadores Genéticos , Haplotipos , Humanos , Polimorfismo de Longitud del Fragmento de RestricciónAsunto(s)
Adenosina Trifosfatasas/genética , Proteínas Portadoras/genética , Proteínas de Transporte de Catión/genética , Trastornos Distónicos/genética , Proteínas Recombinantes de Fusión , Adenosina Trifosfatasas/metabolismo , Adulto , Anciano , Proteínas Portadoras/metabolismo , Proteínas de Transporte de Catión/metabolismo , Cobre/metabolismo , ATPasas Transportadoras de Cobre , Trastornos Distónicos/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , MutaciónRESUMEN
A genetic association between NOTCH4 and schizophrenia has previously been proposed. Unsing all markers previously shown to be associated, we found no evidence for such in three independent family-based samples (n=519 parent-offspring trios), and a case-control sample derived from the same ethnic background as the original observation. These data strongly suggest that NOTCH4 is not a significant susceptibility allele for schizophrenia.
Asunto(s)
Desequilibrio de Ligamiento , Proteínas Proto-Oncogénicas/genética , Receptores de Superficie Celular , Esquizofrenia/genética , Estudios de Casos y Controles , Cromosomas Humanos Par 6 , Genética de Población , Humanos , Repeticiones de Microsatélite , Polimorfismo Genético , Receptor Notch4 , Receptores Notch , Reino UnidoRESUMEN
Mutations in the Wilson disease gene ATP7B, a P-type ATPase, are responsible for copper accumulation in the liver and other organs leading to Wilson disease (WD, OMIM 277900). Clinical manifestations of Wilson disease (WD) include chronic liver disease, acute hepatic failure or neuropsychiatric diseases. Since potent medical treatments are available to prevent disabling residual symptoms, early diagnosis is crucial. To demonstrate the clinical course and genetic findings, a male patient with a novel mutation in the ATP7B gene, a 10 base pair insertion in exon 6 (1927ins 10), and a second missense mutation in exon 13 (P992L) is reported. The patient presented with signs of chronic liver disease at the age of 10 years. Clinical findings included hepatomegaly, elevated liver enzymes and coagulopathy. A combination treatment with the copper chelating agent D-penicillamine and zinc acetate was started leading to normalization of liver function and no appearance of neurological signs or Kayser-Fleischer ring after 7 years follow-up. Truncating mutations of the ATP7B gene (insertions, deletions, nonsense mutations) leading to gross loss of C-terminal parts of the protein, thereby probably completely destroying the protein function, may correlate with a hepatic phenotype and early onset as seen in the patient presented.