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Título :	Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome
Creador:	Engelhardt KR
Nivel de acceso:	Open access
Palabras clave :	Genes Recesivos - genética - niño Estudio de Asociación del Genoma Completo - métodos - niño Factores de Intercambio de Guanina Nucleótido - genética - niño Haplotipos - genética - niño Homocigoto Síndrome de Job - genética - child Síndrome de Job - inmunologia - child Síndrome de Job - patología - child Mutación Puntual - genética - child Polimorfismo de Nucleótido Simple - genética - child Eliminación de Secuencia - genética - child Linfocitos T - inmunologia - niño Genes, Recessive - genetics - child Genome-Wide Association Study - methods - child Guanine Nucleotide Exchange Factors - genetics - child Haplotypes - genetics - child Homozygote Job Syndrome - genetics - child Job Syndrome - immunology - child Job Syndrome - pathology - child Lymphocyte Activation - genetics - child Lymphocyte Activation - immunology - child Point Mutation genetics - child Polymorphism, Single Nucleotide - genetics - child Sequence Deletion - genetics - child T-Lymphocytes - immunology - child Síndrome autosómico recesivo hiperactivo-IgE, gen humano, mutación, DOCK8, inmunodeficiencia primaria, molusco contagioso, infección recurrente, Células TT, Células TH17, eosinófilos, Regulación de IgE, variaciones de número de copia, deleciones genómicas Autosomal recessive hyper-IgE syndrome, human gene mutation, DOCK8, primary immunodeficiency, molluscum contagiosum, recurrent infection, T cells, TH17 cells, eosinophils, IgE regulation, copy number variations, genomic deletions
Descripción :	The genetic etiologies of the hyper-IgE syndromes are diverse. Approximately 60% to 70% of patients with hyper-IgE syndrome have dominant mutations in STAT3, and a single patient was reported to have a homozygous TYK2 mutation. In the remaining patients with hyper-IgE syndrome, the genetic etiology has not yet been identified. OBJECTIVES: We aimed to identify a gene that is mutated or deleted in autosomal recessive hyper-IgE syndrome. METHODS: We performed genome-wide single nucleotide polymorphism analysis for 9 patients with autosomal-recessive hyper-IgE syndrome to locate copy number variations and homozygous haplotypes. Homozygosity mapping was performed with 12 patients from 7 additional families. The candidate gene was analyzed by genomic and cDNA sequencing to identify causative alleles in a total of 27 patients with autosomal-recessive hyper-IgE syndrome. RESULTS: Subtelomeric biallelic microdeletions were identified in 5 patients at the terminus of chromosome 9p. In all 5 patients, the deleted interval involved dedicator of cytokinesis 8 (DOCK8), encoding a protein implicated in the regulation of the actin cytoskeleton. Sequencing of patients without large deletions revealed 16 patients from 9 unrelated families with distinct homozygous mutations in DOCK8 causing premature termination, frameshift, splice site disruption, and single exon deletions and microdeletions. DOCK8 deficiency was associated with impaired activation of CD4+ and CD8+T cells. CONCLUSION: Autosomal-recessive mutations in DOCK8 are responsible for many, although not all, cases of autosomal-recessive hyper-IgE syndrome. DOCK8 disruption is associated with a phenotype of severe cellular immunodeficiency characterized by susceptibility to viral infections, atopic eczema, defective T-cell activation and T(h)17 cell differentiation, and impaired eosinophil homeostasis and dysregulation of IgE
Colaborador(es) u otros Autores:	McGhee S Winkler S Sassi A Woellner C Lopez-Herrera G Chen A Kim HS Lloret MG Schulze I Thiel J Pfeifer D Veelken H Niehues T Siepermann K Weinspach S Reisli I Keles S Genel F Kutukculer N Camcioğlu Y Somer A Karakoc-Aydiner E Barlan I Gennery A Metin A Degerliyurt A Pietrogrande MC Yeganeh M Baz Z Al-Tamemi S Klein C Puck JM Holland SM McCabe ER Grimbacher B Chatila TA.
Fecha de publicación :	2009
Tipo de publicación:	Artículo
Formato:	pdf
Identificador del Recurso :	10.1016/j.jaci.2009.10.038
Fuente:	J Allergy Clin Immunol 124(6):1289-1302
URI :	http://repositorio.pediatria.gob.mx:8180/handle/20.500.12103/2573
Idioma:	eng
Aparece en las colecciones:	Artículos

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