Novel and atypical splicing mutation in a compound heterozygous UNC13D defect presenting in Familial Hemophagocytic Lymphohistiocytosis triggered by EBV infection

L. Alsina, R. Colobran, M. F. De Sevilla, A. Català, L. Viñas, S. Ricart, A. M. Plaza, S. Lois, M. Juan, R. Pujol-Borrell, M. Martinez-Gallo

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Abstract

Familial Hemophagocytic Lymphohistiocytosis type 3 (FHL3) is a genetic disorder caused by mutations in UNC13D gene, coding the granule priming factor Munc13-4 that intervenes in NK and T cell cytotoxic function. Here we report the case of a 17-month-old girl with prolonged symptomatic EBV infectious mononucleosis and clinical symptoms of hemophagocytic syndrome. In vitro functional analysis pointed to a degranulation defect. The genetic analysis of UNC13D gene identified initially a heterozygous mutation (c.753 + 1G > T) in the donor splice-site that resulted in exon 9 skipping (maternal allele). Mutations in other genes were considered, but additional analysis of UNC13D cDNA revealed in the paternal allele a heterozygous transition from G to A (c.2448 - 13G > A) at the 3' acceptor splice-site in intron 25, generating a new acceptor splice-site that leads to a frameshift and a premature STOP codon. Allele specific amplification of the cDNA confirmed the absence of a functional mRNA from the paternal allele. This case illustrates an atypical compound heterozygous UNC13D mutation affecting the RNA splicing that generates a typical FHL3 phenotype. © 2014 Elsevier Inc.
Original languageEnglish
Pages (from-to)292-297
JournalClinical Immunology
Volume153
Issue number2
DOIs
Publication statusPublished - 1 Jan 2014

Keywords

  • Degranulation defect
  • Familial Hemophagocytic Lymphohistiocytosis type 3 (FHL3)
  • RNA splicing defects
  • UNC13D gene

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