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

• Published in: Clinical immunology (Orlando, Fla.) Fla.), 2014-08, Vol.153 (2), p.292-297
• Main Authors: Alsina, L, Colobran, R, de Sevilla, M.F, Català, A, Viñas, L, Ricart, S, Plaza, A.M, Lois, S, Juan, M, Pujol-Borrell, R, Martinez-Gallo, M
• Format: Article
• Language: English
• Subjects: Allergy and Immunology; Base Sequence; Codon, Nonsense; Degranulation defect; DNA Mutational Analysis; Epstein-Barr virus; Epstein-Barr Virus Infections - complications; Familial Hemophagocytic Lymphohistiocytosis type 3 (FHL3); Female; Frameshift Mutation; Heterozygote; Humans; Infant; Lymphohistiocytosis, Hemophagocytic - etiology; Lymphohistiocytosis, Hemophagocytic - genetics; Membrane Proteins - chemistry; Membrane Proteins - genetics; Models, Molecular; Mutation; Point Mutation; Protein Structure, Tertiary; RNA Splice Sites - genetics; RNA splicing defects; UNC13D gene
• ISSN: 1521-6616; 1521-7035
• DOI: 10.1016/j.clim.2014.04.019

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.