Novel and atypical splicing mutation in a compound heterozygous UNC13D defect presenting in Familial Hemophagocytic Lymphohistiocytosis triggered by EBV infection.
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.
Allergy and Clinical Immunology, Universitat de Barcelona, Barcelona, Spain; Immunology Functional Unit, SJD-Clínic, Barcelona, Spain.
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Alsina
Deparment of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, Spain; Immunology Division Hospital Universitari Vall d'Hebron, Barcelona, Spain; Vall d'Hebron Institut de Recerca, Barcelona, Spain.
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Colobran
Paediatric Department, Universitat de Barcelona, Barcelona, Spain.
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de Sevilla
Hematology Department, Hospital Sant Joan de Déu., Universitat de Barcelona, Barcelona, Spain.
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Català
Deparment of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, Spain.
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Viñas
Paediatric Department, Universitat de Barcelona, Barcelona, Spain.
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Ricart
Allergy and Clinical Immunology, Universitat de Barcelona, Barcelona, Spain; Immunology Functional Unit, SJD-Clínic, Barcelona, Spain.
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Plaza
Research Unit in Translational Bioinformatics in Neurosciences, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
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Lois
Immunology Functional Unit, SJD-Clínic, Barcelona, Spain; Immunology Department, Hospital Clinic, Universitat de Barcelona - IDIBAPS, Barcelona, Spain.
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Juan
Deparment of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, Spain; Immunology Division Hospital Universitari Vall d'Hebron, Barcelona, Spain; Vall d'Hebron Institut de Recerca, Barcelona, Spain. Electronic address: ricardo.pujol@uab.cat.
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Pujol-Borrell
Deparment of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, Spain; Immunology Division Hospital Universitari Vall d'Hebron, Barcelona, Spain; Vall d'Hebron Institut de Recerca, Barcelona, Spain.
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Martinez-Gallo
D001483:Base Sequence; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D020031:Epstein-Barr Virus Infections / Q000150:complications*; D005260:Female; D016368:Frameshift Mutation; D006579:Heterozygote; D006801:Humans; D007223:Infant; D051359:Lymphohistiocytosis, Hemophagocytic / Q000209:etiology / Q000235:genetics*; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics*; D008958:Models, Molecular; D009154:Mutation; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D022821:RNA Splice Sites / Q000235:genetics
D018389:Codon, Nonsense; D008565:Membrane Proteins; D022821:RNA Splice Sites; C507969:UNC13D protein, human
Degranulation defect; Familial Hemophagocytic Lymphohistiocytosis type 3 (FHL3); RNA splicing defects; UNC13D gene