scholarly journals Familial Hemophagocytic Lymphohistiocytosis Type 3: Early Disease Onset and Unusual Manifestation in Sibling Cases

2019 ◽  
Vol In Press (In Press) ◽  
Author(s):  
Junbin Huang ◽  
Li Jiang ◽  
Xiaojun Wu ◽  
Yucai Cheng ◽  
Chun Chen ◽  
...  
Keyword(s):  
Hemophagocytic Lymphohistiocytosis ◽  
Disease Onset ◽  
Early Disease ◽  
Unusual Manifestation ◽  
Familial Hemophagocytic Lymphohistiocytosis ◽  
Type 3 ◽  
Sibling Cases

scholarly journals Jinx, an MCMV susceptibility phenotype caused by disruption of Unc13d: a mouse model of type 3 familial hemophagocytic lymphohistiocytosis

2007 ◽  
Vol 204 (4) ◽  
pp. 853-863 ◽  
Author(s):  
Karine Crozat ◽  
Kasper Hoebe ◽  
Sophie Ugolini ◽  
Nancy A. Hong ◽  
Edith Janssen ◽  
...  
Keyword(s):  
Hemophagocytic Lymphohistiocytosis ◽  
Cell Function ◽  
Nk Cell ◽  
Lymphocytic Choriomeningitis ◽  
Chromosome 11 ◽  
Familial Hemophagocytic Lymphohistiocytosis ◽  
Cytokine Levels ◽  
Antigen Presenting ◽  
Type 3 ◽  
Mouse Chromosome 11

Mouse cytomegalovirus (MCMV) susceptibility often results from defects of natural killer (NK) cell function. Here we describe Jinx, an N-ethyl-N-nitrosourea–induced MCMV susceptibility mutation that permits unchecked proliferation of the virus, causing death. In Jinx homozygotes, activated NK cells and cytotoxic T lymphocytes (CTLs) fail to degranulate, although they retain the ability to produce cytokines, and cytokine levels are markedly elevated in the blood of infected mutant mice. Jinx was mapped to mouse chromosome 11 on a total of 246 meioses and confined to a 4.60–million basepair critical region encompassing 122 annotated genes. The phenotype was ascribed to the creation of a novel donor splice site in Unc13d, the mouse orthologue of human MUNC13-4, in which mutations cause type 3 familial hemophagocytic lymphohistiocytosis (FHL3), a fatal disease marked by massive hepatosplenomegaly, anemia, and thrombocytopenia. Jinx mice do not spontaneously develop clinical features of hemophagocytic lymphohistiocytosis (HLH), but do so when infected with lymphocytic choriomeningitis virus, exhibiting hyperactivation of CTLs and antigen-presenting cells, and inadequate restriction of viral proliferation. In contrast, neither Listeria monocytogenes nor MCMV induces the syndrome. In mice, the HLH phenotype is conditional, which suggests the existence of a specific infectious trigger of FHL3 in humans.

FATAL SIBLING CASES OF FAMILIAL HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (FHL) WITH MUNC13–4 MUTATIONS: Case Reports

2008 ◽  
Vol 25 (3) ◽  
pp. 171-180 ◽  
Author(s):  
Tomohei Nakao ◽  
Takashi Shimizu ◽  
Takashi Fukushima ◽  
Makoto Saito ◽  
Miho Okamoto ◽  
...  
Keyword(s):  
Hemophagocytic Lymphohistiocytosis ◽  
Case Reports ◽  
Familial Hemophagocytic Lymphohistiocytosis ◽  
Sibling Cases

Retroviral UNC13D Gene Transfer Restores Cytotoxic Activity of T Cells Derived from Familial Hemophagocytic Lymphohistiocytosis Type 3 Patients In Vitro

2019 ◽  
Vol 30 (8) ◽  
pp. 975-984 ◽  
Author(s):  
Viviane Dettmer ◽  
Kristie Bloom ◽  
Miriam Gross ◽  
Kristoffer Weissert ◽  
Peter Aichele ◽  
...  
Keyword(s):  
T Cells ◽  
Gene Transfer ◽  
Cytotoxic Activity ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Familial Hemophagocytic Lymphohistiocytosis ◽  
Type 3

scholarly journals A CD57+ CTL Degranulation Assay Effectively Identifies Familial Hemophagocytic Lymphohistiocytosis Type 3 Patients

2016 ◽  
Vol 37 (1) ◽  
pp. 92-99 ◽  
Author(s):  
Masayuki Hori ◽  
Takahiro Yasumi ◽  
Saeko Shimodera ◽  
Hirofumi Shibata ◽  
Eitaro Hiejima ◽  
...  
Keyword(s):  
Hemophagocytic Lymphohistiocytosis ◽  
Familial Hemophagocytic Lymphohistiocytosis ◽  
Type 3

scholarly journals Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) caused by deep intronic mutation and inversion in UNC13D

Blood ◽  
2011 ◽  
Vol 118 (22) ◽  
pp. 5783-5793 ◽  
Author(s):  
Marie Meeths ◽  
Samuel C. C. Chiang ◽  
Stephanie M. Wood ◽  
Miriam Entesarian ◽  
Heinrich Schlums ◽  
...  
Keyword(s):  
Hemophagocytic Lymphohistiocytosis ◽  
Autosomal Recessive ◽  
Northern Europe ◽  
Splice Sites ◽  
Specific Expression ◽  
Familial Hemophagocytic Lymphohistiocytosis ◽  
Intronic Mutation ◽  
Intron 1 ◽  
Cell Type Specific Expression ◽  
Type 3

Abstract Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive, often-fatal hyperinflammatory disorder. Mutations in PRF1, UNC13D, STX11, and STXBP2 are causative of FHL2, 3, 4, and 5, respectively. In a majority of suspected FHL patients from Northern Europe, sequencing of exons and splice sites of such genes required for lymphocyte cytotoxicity revealed no or only monoallelic UNC13D mutations. Here, in 21 patients, we describe 2 pathogenic, noncoding aberrations of UNC13D. The first is a point mutation localized in an evolutionarily conserved region of intron 1. This mutation selectively impairs UNC13D transcription in lymphocytes, abolishing Munc13-4 expression. The second is a 253-kb inversion straddling UNC13D, affecting the 3′-end of the transcript and likewise abolishing Munc13-4 expression. Carriership of the intron 1 mutation was found in patients across Europe, whereas carriership of the inversion was limited to Northern Europe. Notably, the latter aberration represents the first description of an autosomal recessive human disease caused by an inversion. These findings implicate an intronic sequence in cell-type specific expression of Munc13-4 and signify variations outside exons and splice sites as a common cause of FHL3. Based on these data, we propose a strategy for targeted sequencing of evolutionary conserved noncoding regions for the diagnosis of primary immunodeficiencies.

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