HOME HELP FEEDBACK TABLE OF CONTENTS ARCHIVE SUBSCRIPTIONS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Santoro et al. - Supplementary Appendix Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Santoro, A. Articles by Aricò, M. PubMed PubMed Citation Articles by Santoro, A. Articles by Aricò, M.

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

¹ Divisione di Ematologia I, A.O. V. Cervello, Palermo, Italy
² Onco Ematologia Pediatrica, Ospedale dei Bambini "G. Di Cristina", Palermo, Italy
³ Onco Ematologia Pediatrica, Ospedale Pausilipon, Napoli, Italy
⁴ Division of Immunology, Children’s Hospital, Harvard Medical School, Boston, USA
⁵ Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
⁶ Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Cambridge, UK
⁷ Oncoematologia Pediatrica, A.O.U. Meyer, Firenze, Italy

Correspondence: Maurizio Aricò, U.O. Oncoematologia Pediatrica, Azienda Ospedaliero-Universitaria Meyer, viale Pieraccini, 24, 50139 Firenze, Italy. E-mail:m.arico{at}meyer.it

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.