A novel Dutch mutation in UNC13D reveals an essential role of the C2B domain in munc13-4 function

Edo D. Elstak, Maroeska Te Loo, Kiki Tesselaar, Peter Van Kerkhof, Jan Loeffen, Dimitris Grivas, Eric Hennekam, Jaap Jan Boelens, Peter M. Hoogerbrugge, Peter Van der Sluijs, Marielle E. Van Gijn, Lisette Van de Corput

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

7 Citaten (Scopus)


Background: UNC13D, encoding the protein munc13-4, is essential in intracellular trafficking and exocytosis of lytic granules. Mutations in this gene are associated with familial hemophagocytic lymphohistiocytosis type 3 (FHL3), a genetically heterogeneous, rare autosomal recessive immune disorder. How mutations affect function of munc13-4 is poorly understood. Since 2006 we genetically identified seven FHL patients with mutations in UNC13D. Procedures: Here, we report for the first time a c.2695C>T (p.Arg899X) mutation in exon 28 of UNC13D in three young unrelated Dutch patients. The mutation causes a premature stop codon and encodes munc13-4(1-899), which lacks the C-terminal C2 domain. Genealogical research and haplotyping of the patient families demonstrated that a single ancestral founder introduced the mutation in the Netherlands. We then characterized the mutant protein phenotypically in cell biological and immunological assays. Results: Munc13-4(1-899) was correctly targeted to CD63-positive secretory lysosomes, although its stability was reduced and dynamic turnover on the granule membrane became uncoupled from receptor signaling. In accord, and in contrast to wild-type munc13-4, ectopically expressed mutant failed to rescue degranulation in cells with silenced endogenous munc13-4. Conclusions: The functional and clinical data showed that this novel Dutch founder mutation leads to severe early onset of FHL3 due to misfolding and degradation of munc13-4(1-899).

Originele taal-2Engels
Pagina's (van-tot)598-605
Aantal pagina's8
TijdschriftPediatric Blood and Cancer
Nummer van het tijdschrift4
StatusGepubliceerd - apr. 2012
Extern gepubliceerdJa


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