Novel Munc13-4 mutations in children and young adult patients with haemophagocytic lymphohistiocytosis

Santoro, Alessandra; Cannella, Sonia; Bossi, Giovanna; Gallo, Federico; Trizzino, Antonino; Pende, Daniela; Dieli, Francesco; Bruno, Giuseppa; Stinchcombe, Jane C.; Micalizzi, Concetta; Fusco, Carmela; Danesino, Cesare; Moretta, Alessandro; Notarangelo, LD; Griffiths, Gillian M.; Aricò, Maurizio

doi:10.1136/jmg.2006.041863

Cited by 75 publications

(68 citation statements)

References 32 publications

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“…Interestingly, one patient with primary HLH and no apparent disease trigger harbored a Munc13-4 mutation. Although familial HLH is rare in adults, recent reports suggest that late-onset familial HLH occurs more commonly than was previously suspected [24], including Munc13-4 gene mutations in young adults [24,25]. This finding has important clinical implications as patients with familial HLH typically require stem cell transplantation.…”

Section: Discussionmentioning

confidence: 83%

Clinical characteristics, prognostic factors, and outcomes of adult patients with hemophagocytic lymphohistiocytosis

2015

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Hemophagocytic lymphohistiocytosis (HLH) is a rare clinical syndrome characterized by the activation of the mononuclear phagocytic system. The diagnosis of HLH in adults is challenging not only because the majority of the reported data are from pediatric patients, but also because HLH occurs in many disease entities. This study reports the clinical and laboratory findings and prognostic factors of adult HLH in a large cohort managed at a single medical center from 2003 to 2014. Seventy-three patients met the HLH-2004 diagnostic criteria. The median age was 51 years (range, 18-82 years); 41 (56.2%) were male. Patients manifested fever, cytopenias, and elevated ferritin in >85% of cases. Likely causes of HLH were as follows: 30 (41.1%) infections, 21 (28.8%) malignancies, 5 (6.8%) attributed to autoimmune disorders, 1 (1.4%) primary immunodeficiency, 2 (2.7%) post solid organ transplantation, and 13 (17.8%) idiopathic. The median overall survival was 7.67 months. Patients with malignancy-associated HLH had a markedly worse survival compared with patients with non-malignancy-associated HLH (median overall survival 1.13 vs. 46.53 months, respectively; P < 0.0001). In a multivariable analysis, malignancy (hazard ratio 5 12.22; 95% CI: 2.53-59.02; P 5 0.002) correlated with poor survival. Ferritin >50,000 mg/L correlated with 30-day mortality. Survival after a diagnosis of HLH is dismal, especially among those with malignancy-associated HLH. The development of a registry for adults with HLH would improve our understanding of this syndrome, validate diagnostic criteria, and help develop effective treatment strategies.

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Section: Discussionmentioning

confidence: 83%

Clinical characteristics, prognostic factors, and outcomes of adult patients with hemophagocytic lymphohistiocytosis

2015

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“…Only 2 of them, 753+1G>T and 1389+1G>A, had been already reported by other groups. The remaining 5 have only been observed in our patients: the 610A>G (M204V) and 1847A>G (E616G) (included in our recent report), 20 the previously unreported 952-1G>A, and in two families we found an allele containing deep (>10nt from the exon/intron boundary) intronic mutations (one had IVS1 +59C>T, +394C>T, +525G>T, and the other had IVS30+431delA).…”

Section: Resultsmentioning

confidence: 90%

Mutations affecting mRNA splicing are the most common molecular defect in patients with familial hemophagocytic lymphohistiocytosis type 3

Santoro¹,

Cannella

Trizzino

et al. 2008

Haematologica

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Mutations of UNC13D have been described in patients affected by familial hemophagocytic lymphohistiocytosis (FHL3). The Munc13-4 protein contributes to the priming of the secretory granules. Mutation in this gene results in defective cellular cytotoxicity and the familial hemophagocytic lymphohistiocytosis clinical picture. Among reported mutations, few are predicted to impair splicing. Yet, functional impact of these mutations has not been addressed. We identified 18 out of 31 familial hemophagocytic lymphohistiocytosis families showing at least one mutation responsible for splicing error. We identified some known and three novel splicing mutations: one falls at the acceptor site of exon 11 and 2 are deep intronic mutations in IVS1 and in IVS30. We demonstrated that these deep intronic mutations affect regulatory sequences causing aberrant splicing. We report that UNC13D mutations leading to splicing errors represent the majority of mutations observed in familial hemophagocytic lymphohistiocytosis. This finding has implications for designing strategies for analysis of the families with suspected familial hemophagocytic lymphohistiocytosis.Key words: lymphohistiocytosis, splicing.

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“…Our data also showed that there is no mutation hotspot in UNC13D, implying that all coding exons and flanking intronic sequences must be screened. 18,30 Of note, half of the patients with UNC13D mutations in our series (4/8) had only one mutant allele (Table 1). Considering the autosomal recessive inheritance, we speculated that there would be a hidden mutation missed by conventional direct sequencing.…”

confidence: 99%

UNC13D is the predominant causative gene with recurrent splicing mutations in Korean patients with familial hemophagocytic lymphohistiocytosis

Yoon¹,

Kim²,

Yoo³

et al. 2009

Haematologica

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Novel Munc13-4 mutations in children and young adult patients with haemophagocytic lymphohistiocytosis

Cited by 75 publications

References 32 publications

Clinical characteristics, prognostic factors, and outcomes of adult patients with hemophagocytic lymphohistiocytosis

Clinical characteristics, prognostic factors, and outcomes of adult patients with hemophagocytic lymphohistiocytosis

Mutations affecting mRNA splicing are the most common molecular defect in patients with familial hemophagocytic lymphohistiocytosis type 3

UNC13D is the predominant causative gene with recurrent splicing mutations in Korean patients with familial hemophagocytic lymphohistiocytosis

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