UNC13D explained

Protein unc-13 homolog D, also known as munc13-4, is a protein that in humans is encoded by the UNC13D gene.^[1]

Function

Munc13-4 is a member of the UNC13 family, containing similar domain structure as other family members but lacking an N-terminal phorbol ester-binding C1 domain present in other Munc13 proteins. The protein appears to play a role in vesicle maturation during exocytosis and is involved in regulation of cytolytic granules secretion.

Clinical significance

Mutations in the UNC13D gene are associated with hemophagocytic lymphohistiocytosis type 3.^[1]

Further reading

• Marcenaro S, Gallo F, Martini S, etal . Analysis of natural killer-cell function in familial hemophagocytic lymphohistiocytosis (FHL): defective CD107a surface expression heralds Munc13-4 defect and discriminates between genetic subtypes of the disease. . Blood . 108 . 7 . 2316–23 . 2006 . 16778144 . 10.1182/blood-2006-04-015693 . free .
• Gurgey A, Unal S, Okur H, etal . Neonatal primary hemophagocytic lymphohistiocytosis in Turkish children. . J. Pediatr. Hematol. Oncol. . 30 . 12 . 871–6 . 2008 . 19131769 . 10.1097/MPH.0b013e31818a9577 . 25882775 .
• Saxena SK, Horiuchi H, Fukuda M . Rab27a regulates epithelial sodium channel (ENaC) activity through synaptotagmin-like protein (SLP-5) and Munc13-4 effector mechanism. . Biochem. Biophys. Res. Commun. . 344 . 2 . 651–7 . 2006 . 16630545 . 10.1016/j.bbrc.2006.03.160 .
• Neeft M, Wieffer M, de Jong AS, etal . Munc13-4 is an effector of rab27a and controls secretion of lysosomes in hematopoietic cells. . Mol. Biol. Cell . 16 . 2 . 731–41 . 2005 . 15548590 . 10.1091/mbc.E04-10-0923 . 545907.
• Ménager MM, Ménasché G, Romao M . Secretory cytotoxic granule maturation and exocytosis require the effector protein hMunc13-4. . Nat. Immunol. . 8 . 3 . 257–67 . 2007 . 17237785 . 10.1038/ni1431 . 25330412 . etal.
• Santoro A, Cannella S, Trizzino A, etal . Mutations affecting mRNA splicing are the most common molecular defect in patients with familial hemophagocytic lymphohistiocytosis type 3. . Haematologica . 93 . 7 . 1086–90 . 2008 . 18492689 . 10.3324/haematol.12622 . free .
• Zhang K, Biroschak J, Glass DN, etal . Macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis is associated with MUNC13-4 polymorphisms. . Arthritis Rheum. . 58 . 9 . 2892–6 . 2008 . 18759271 . 10.1002/art.23734 . 2779064.
• Yoon HS, Kim HJ, Yoo KH, etal . UNC13D is the predominant causative gene with recurrent splicing mutations in Korean patients with familial hemophagocytic lymphohistiocytosis. . Haematologica . 95 . 4 . 622–6 . 2010 . 20015888 . 10.3324/haematol.2009.016949 . 2857192.
• Horne A, Ramme KG, Rudd E, etal . Characterization of PRF1, STX11 and UNC13D genotype-phenotype correlations in familial hemophagocytic lymphohistiocytosis. . Br. J. Haematol. . 143 . 1 . 75–83 . 2008 . 18710388 . 10.1111/j.1365-2141.2008.07315.x . 2773353 . free .
• Zur Stadt U, Beutel K, Kolberg S, etal . Mutation spectrum in children with primary hemophagocytic lymphohistiocytosis: molecular and functional analyses of PRF1, UNC13D, STX11, and RAB27A. . Hum. Mutat. . 27 . 1 . 62–8 . 2006 . 16278825 . 10.1002/humu.20274 . 19226893 . free .
• Rudd E, Bryceson YT, Zheng C, etal . Spectrum, and clinical and functional implications of UNC13D mutations in familial haemophagocytic lymphohistiocytosis. . J. Med. Genet. . 45 . 3 . 134–41 . 2008 . 17993578 . 10.1136/jmg.2007.054288 . 42503634 .
• Beutler B . Microbe sensing, positive feedback loops, and the pathogenesis of inflammatory diseases. . Immunol. Rev. . 227 . 1 . 248–63 . 2009 . 19120489 . 10.1111/j.1600-065X.2008.00733.x . 2713013.
• Nakao T, Shimizu T, Fukushima T, etal . Fatal sibling cases of familial hemophagocytic lymphohistiocytosis (FHL) with MUNC13-4 mutations: case reports. . Pediatr Hematol Oncol . 25 . 3 . 171–80 . 2008. 18432499 . 10.1080/08880010801938082 . 205600908 .
• Donn R, Ellison S, Lamb R, etal . Genetic loci contributing to hemophagocytic lymphohistiocytosis do not confer susceptibility to systemic-onset juvenile idiopathic arthritis. . Arthritis Rheum. . 58 . 3 . 869–74 . 2008 . 18311812 . 10.1002/art.23270 . 2675009.
• Hazen MM, Woodward AL, Hofmann I, etal . Mutations of the hemophagocytic lymphohistiocytosis-associated gene UNC13D in a patient with systemic juvenile idiopathic arthritis. . Arthritis Rheum. . 58 . 2 . 567–70 . 2008 . 18240215 . 10.1002/art.23199 . free .
• Santoro A, Cannella S, Bossi G, etal . Novel Munc13-4 mutations in children and young adult patients with haemophagocytic lymphohistiocytosis. . J. Med. Genet. . 43 . 12 . 953–60 . 2006 . 16825436 . 10.1136/jmg.2006.041863 . 2563207.
• Pivot-Pajot C, Varoqueaux F, de Saint Basile G, Bourgoin SG . Munc13-4 regulates granule secretion in human neutrophils. . J. Immunol. . 180 . 10 . 6786–97 . 2008 . 18453599 . 10.4049/jimmunol.180.10.6786. free .
• Wood SM, Meeths M, Chiang SC, etal . Different NK cell-activating receptors preferentially recruit Rab27a or Munc13-4 to perforin-containing granules for cytotoxicity. . Blood . 114 . 19 . 4117–27 . 2009 . 19704116 . 10.1182/blood-2009-06-225359 . free .
• Zhong N, Radu G, Ju W, Brown WT . Novel progerin-interactive partner proteins hnRNP E1, EGF, Mel 18, and UBC9 interact with lamin A/C. . Biochem. Biophys. Res. Commun. . 338 . 2 . 855–61 . 2005 . 16248985 . 10.1016/j.bbrc.2005.10.020 .
• Chang TY, Jaffray J, Woda B, etal . Hemophagocytic lymphohistiocytosis with MUNC13-4 gene mutation or reduced natural killer cell function prior to onset of childhood leukemia. . Pediatr Blood Cancer . 56 . 5 . 856–8 . 2011 . 21370424 . 10.1002/pbc.22846 . 3059114.

Notes and References

1. Web site: Entrez Gene: unc-13 homolog D (C. elegans).