Combined germline and somatic human FADD mutations cause autoimmune lymphoproliferative syndrome.
J Allergy Clin Immunol
; 153(1): 203-215, 2024 01.
Article
em En
| MEDLINE
| ID: mdl-37793571
ABSTRACT
BACKGROUND:
The autoimmune lymphoproliferative syndrome (ALPS) is a noninfectious and nonmalignant lymphoproliferative disease frequently associated with autoimmune cytopenia resulting from defective FAS signaling. We previously described germline monoallelic FAS (TNFRSF6) haploinsufficient mutations associated with somatic events, such as loss of heterozygosity on the second allele of FAS, as a cause of ALPS-FAS. These somatic events were identified by sequencing FAS in DNA from double-negative (DN) T cells, the pathognomonic T-cell subset in ALPS, in which the somatic events accumulated.OBJECTIVE:
We sought to identify whether a somatic event affecting the FAS-associated death domain (FADD) gene could be related to the disease onset in 4 unrelated patients with ALPS carrying a germline monoallelic mutation of the FADD protein inherited from a healthy parent.METHODS:
We sequenced FADD and performed array-based comparative genomic hybridization using DNA from sorted CD4+ or DN T cells.RESULTS:
We found homozygous FADD mutations in the DN T cells from all 4 patients, which resulted from uniparental disomy. FADD deficiency caused by germline heterozygous FADD mutations associated with a somatic loss of heterozygosity was a phenocopy of ALPS-FAS without the more complex symptoms reported in patients with germline biallelic FADD mutations.CONCLUSIONS:
The association of germline and somatic events affecting the FADD gene is a new genetic cause of ALPS.Palavras-chave
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Bases de dados:
MEDLINE
Assunto principal:
Proteína de Domínio de Morte Associada a Fas
/
Síndrome Linfoproliferativa Autoimune
Limite:
Humans
Idioma:
En
Revista:
J Allergy Clin Immunol
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
França