Fatal immune dysregulation due to a gain of glycosylation mutation in lymphocyte perforin.
Blood
; 119(7): 1713-6, 2012 Feb 16.
Article
em En
| MEDLINE
| ID: mdl-22186995
ABSTRACT
Mutations in the perforin gene (PRF1) are a common cause of the fatal immune dysregulation disorder, familial hemophagocytic lymphohistiocytosis (type 2 FHL, FHL2). Here we report a female infant born with biallelic PRF1 mutations a novel substitution, D49N, and a previously identified in-frame deletion, K285del. We assessed the effects of each mutation on the cytotoxicity of human NK cells in which the expression of endogenous perforin was ablated with miR30-based short hairpin (sh) RNAs. Both mutations were detrimental for function, thereby explaining the clinically severe presentation and rapidly fatal outcome. We demonstrate that D49N exerts its deleterious effect by generating an additional (third) N-linked glycosylation site, resulting in protein misfolding and degradation in the killer cell. Our data provide a rationale for treating some cases of type 2 familial hemophagocytic lymphohistiocytosis, based on the pharmacologic inhibition or modification of glycosylation.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Linfócitos
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Mutação de Sentido Incorreto
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Proteínas Citotóxicas Formadoras de Poros
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Doenças do Sistema Imunitário
Tipo de estudo:
Prognostic_studies
Limite:
Female
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Humans
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Newborn
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article