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

Alessandra Santoro, Sonia Cannella, Antonino Trizzino, Giuseppa Bruno, Carmen De Fusco, Luigi D. Notarangelo, Daniela Pende, Gillian M. Griffiths, Maurizio Aricò

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)1086-1090
Number of pages5
JournalHaematologica
Volume93
Issue number7
DOIs
Publication statusPublished - Jul 2008

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Keywords

  • Lymphohistiocytosis
  • Splicing

ASJC Scopus subject areas

  • Hematology

Cite this

Santoro, A., Cannella, S., Trizzino, A., Bruno, G., De Fusco, C., Notarangelo, L. D., Pende, D., Griffiths, G. M., & Aricò, M. (2008). Mutations affecting mRNA splicing are the most common molecular defect in patients with familial hemophagocytic lymphohistiocytosis type 3. Haematologica, 93(7), 1086-1090. https://doi.org/10.3324/haematol.12622