RESUMEN
TNFRSF13B encodes transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), a B cell- specific tumor necrosis factor (TNF) receptor superfamily member. Both biallelic and monoallelic TNFRSF13B mutations were identified in patients with common variable immunodeficiency disorders. The genetic complexity and variable clinical presentation of TACI deficiency prompted us to evaluate the genetic, immunologic, and clinical condition in 50 individuals with TNFRSF13B alterations, following screening of 564 unrelated patients with hypogammaglobulinemia. We identified 13 new sequence variants. The most frequent TNFRSF13B variants (C104R and A181E; n=39; 6.9%) were also present in a heterozygous state in 2% of 675 controls. All patients with biallelic mutations had hypogammaglobulinemia and nearly all showed impaired binding to a proliferation-inducing ligand (APRIL). However, the majority (n=41; 82%) of the pa-tients carried monoallelic changes in TNFRSF13B. Presence of a heterozygous mutation was associated with antibody deficiency (P< .001, relative risk 3.6). Heterozygosity for the most common mutation, C104R, was associated with disease (P< .001, relative risk 4.2). Furthermore, heterozygosity for C104R was associated with low numbers of IgD(-)CD27(+) B cells (P= .019), benign lymphoproliferation (P< .001), and autoimmune complications (P= .001). These associations indicate that C104R heterozygosity increases the risk for common variable immunodeficiency disorders and influences clinical presentation.
Asunto(s)
Agammaglobulinemia/genética , Predisposición Genética a la Enfermedad/genética , Mutación , Proteína Activadora Transmembrana y Interactiva del CAML/genética , Alelos , Sustitución de Aminoácidos , Estudios de Casos y Controles , Células Cultivadas , Estudios de Cohortes , Análisis Mutacional de ADN , Frecuencia de los Genes , Heterocigoto , Homocigoto , Humanos , Mutación/fisiología , Linaje , Polimorfismo de Nucleótido Simple/fisiología , Factores de Riesgo , SíndromeRESUMEN
BACKGROUND: Common variable immunodeficiency (CVID) comprises a heterogeneous group of primary antibody deficiencies with complex clinical and immunological phenotypes. The recent discovery that some CVID patients show monogenic defects in the genes encoding ICOS, TACI or CD19 prompted us to investigate several functional candidate genes in individuals with CVID. RESULTS: The exonic, protein coding regions of the genes encoding: APRIL, BCMA, IL10, IL10Ralpha, IL10Rbeta, IL21, IL21R, and CCL18, were analyzed primarily in familial CVID cases, who showed evidence of genetic linkage to the respective candidate gene loci and CVID families with a recessive pattern of inheritance. Two novel SNPs were identified in exon 5 and exon 8 of the IL21R gene, which segregated with the disease phenotype in one CVID family. Eleven additional SNPs in the genes encoding BCMA, APRIL, IL10, IL10Ralpha, IL21 and IL21R were observed at similar frequencies as in healthy donors. CONCLUSION: We were unable to identify obvious disease causing mutations in the protein coding regions of the analyzed genes in the studied cohort.
Asunto(s)
Inmunodeficiencia Variable Común/genética , Pruebas Genéticas , Antígeno de Maduración de Linfocitos B/genética , Quimiocinas CC/genética , Familia , Femenino , Humanos , Interleucina-10/genética , Subunidad alfa del Receptor de Interleucina-10/genética , Interleucinas/genética , Masculino , Linaje , Polimorfismo de Nucleótido Simple/genética , Receptores de Interleucina-21/genética , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/genéticaRESUMEN
We report the case of an infant with severe respiratory infections, chronic diarrhea, failure to thrive, and disseminated Cryptosporidium parvum infection. Laboratory investigations disclosed a diagnosis of hyper-IgM syndrome caused by CD40 deficiency.
Asunto(s)
Antígenos CD40/genética , Criptosporidiosis/etiología , Enfermedades Genéticas Ligadas al Cromosoma X/complicaciones , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Hipergammaglobulinemia/complicaciones , Hipergammaglobulinemia/genética , Inmunoglobulina M/genética , Consanguinidad , Diagnóstico Diferencial , Femenino , Citometría de Flujo , Genes Recesivos/genética , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Enfermedades Genéticas Ligadas al Cromosoma X/terapia , Trastornos del Crecimiento/etiología , Humanos , Hipergammaglobulinemia/diagnóstico , Hipergammaglobulinemia/terapia , Inmunofenotipificación , Lactante , Linaje , Insuficiencia Respiratoria/etiología , Tomografía Computarizada por Rayos X , TurquíaRESUMEN
UNLABELLED: Common variable immunodeficiency (CVID) and X-linked lymphoproliferative (XLP) disease are two immunodeficiencies that may share a similar immunological phenotype making differential diagnosis difficult. We report two patients initially diagnosed as affected with CVID who, using molecular analysis, have been subsequently found to be affected with XLP disease. Distinguishing between these two diseases is essential since they have different prognosis, treatment and genetic counselling. CONCLUSION: current techniques, such as genetic analysis of the SH2D1A gene and expression of signalling lymphocyte activation molecule-associated protein, allow a definite diagnosis of X-linked lymphoproliferative disease.