Germline TET2 loss of function causes childhood immunodeficiency and lymphoma.
Blood
; 136(9): 1055-1066, 2020 08 27.
Article
en En
| MEDLINE
| ID: mdl-32518946
Molecular dissection of inborn errors of immunity can help to elucidate the nonredundant functions of individual genes. We studied 3 children with an immune dysregulation syndrome of susceptibility to infection, lymphadenopathy, hepatosplenomegaly, developmental delay, autoimmunity, and lymphoma of B-cell (n = 2) or T-cell (n = 1) origin. All 3 showed early autologous T-cell reconstitution following allogeneic hematopoietic stem cell transplantation. By whole-exome sequencing, we identified rare homozygous germline missense or nonsense variants in a known epigenetic regulator of gene expression: ten-eleven translocation methylcytosine dioxygenase 2 (TET2). Mutated TET2 protein was absent or enzymatically defective for 5-hydroxymethylating activity, resulting in whole-blood DNA hypermethylation. Circulating T cells showed an abnormal immunophenotype including expanded double-negative, but depleted follicular helper, T-cell compartments and impaired Fas-dependent apoptosis in 2 of 3 patients. Moreover, TET2-deficient B cells showed defective class-switch recombination. The hematopoietic potential of patient-derived induced pluripotent stem cells was skewed toward the myeloid lineage. These are the first reported cases of autosomal-recessive germline TET2 deficiency in humans, causing clinically significant immunodeficiency and an autoimmune lymphoproliferative syndrome with marked predisposition to lymphoma. This disease phenotype demonstrates the broad role of TET2 within the human immune system.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Proteínas Proto-Oncogénicas
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Inmunodeficiencia Combinada Grave
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Mutación de Línea Germinal
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Proteínas de Unión al ADN
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Mutación con Pérdida de Función
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Trastornos Linfoproliferativos
Tipo de estudio:
Etiology_studies
/
Prognostic_studies
Límite:
Female
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Humans
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Male
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Newborn
Idioma:
En
Revista:
Blood
Año:
2020
Tipo del documento:
Article
País de afiliación:
Reino Unido
Pais de publicación:
Estados Unidos