RESUMEN
We report a novel pathomechanism for membranoproliferative glomerulonephritis type II (MPGN II) caused by a mutant Factor H protein expressed in the plasma. Genetic analyses of two patients revealed deletion of a single Lys residue (K224) located within the complement regulatory region in domain 4 of Factor H. This deletion resulted in defective complement control: mutant protein purified from the plasma of patients showed severely reduced cofactor and decay-accelerating activity, as well as reduced binding to the central complement component C3b. However, cell-binding activity of the mutant protein was normal and comparable to wild-type Factor H. The patients are daughters of consanguineous parents. As both patients but also their healthy mother were positive for C3 nephritic factor, the mutant Factor H protein is considered relevant for unrestricted activation of the disease-causing activation of the alternative complement pathway. Replacement of functional Factor H by fresh frozen plasma (10-15 ml/kg/14 days) was well tolerated, prevented so far disease progression in both patients, and is in the long run expected to preserve kidney function.
Asunto(s)
Factor H de Complemento/genética , Factor H de Complemento/metabolismo , Vía Alternativa del Complemento , Glomerulonefritis Membranoproliferativa/genética , Glomerulonefritis Membranoproliferativa/inmunología , Secuencia de Aminoácidos , Niño , Factor Nefrítico del Complemento 3/análisis , Factor Nefrítico del Complemento 3/metabolismo , Factor H de Complemento/análisis , Consanguinidad , Femenino , Humanos , Lisina/química , Lisina/genética , Datos de Secuencia Molecular , Linaje , Plasma/química , Plasma/metabolismo , Estructura Terciaria de Proteína/genética , Eliminación de SecuenciaRESUMEN
BACKGROUND: Factor (F)XI is important in the consolidation phase of blood coagulation. The structural effects of mutations causing FXI deficiency have not been well described due to the lack of a structure for FXI. OBJECTIVES: To develop molecular models of the four apple (Ap) and serine protease (SP) domains in FXI in order to assess the structural effects of published FXI mutations in the light of their phenotypes. METHODS: The Ap domains were modeled using the NMR structure of an adhesin from Eimeria tenella. The SP domain was modeled using the crystal structure of beta-tryptase. RESULTS: The effect of 42 mutations causing FXI deficiency was analyzed using homology models for the Ap and SP domains in FXI. Protein misfolding was implicated as the likely structural mechanism of disease in six of 14 mutations in the four Ap domains with Type I phenotypes. Likewise, misfolding was implicated in eight of 14 mutations in the SP domain with Type I phenotypes. Unlike other coagulation factor deficiencies, Type II phenotypes based on a catalytically dysfunctional FXI are uncommon. The structural models indicated that two known Type II mutations in the Ap domains could be correlated with functional defects in substrate or cofactor binding, and likewise four Type II mutations in the SP domain would disrupt the active site. CONCLUSIONS: New FXI disease-causing mutations can now be structurally characterized to complement phenotypic data, and expression studies can be designed to verify the molecular basis of each deficiency.
Asunto(s)
Deficiencia del Factor XI/diagnóstico , Deficiencia del Factor XI/genética , Mutación , Secuencia de Aminoácidos , Animales , Antígenos/química , Coagulación Sanguínea , Eimeria tenella , Heterocigoto , Homocigoto , Humanos , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Datos de Secuencia Molecular , Fenotipo , Conformación Proteica , Pliegue de Proteína , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Homología de Secuencia de Aminoácido , Serina Endopeptidasas/químicaAsunto(s)
Dislexia , Logro , Anfetaminas/uso terapéutico , Trastorno por Déficit de Atención con Hiperactividad , Niño , Preescolar , Dislexia/complicaciones , Dislexia/psicología , Dislexia/terapia , Educación Especial , Humanos , Hipercinesia , Psicoterapia , Trastorno de la Conducta Social/etiología , Logopedia , Enseñanza/métodos , Terminología como AsuntoRESUMEN
The polyhedral inclusions of Thiobacillus neapolitanus have been isolated; they contain ribulose diphosphate carboxylase.