{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T06:34:09Z","timestamp":1774852449265,"version":"3.50.1"},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"8","license":[{"start":{"date-parts":[[2022,7,23]],"date-time":"2022-07-23T00:00:00Z","timestamp":1658534400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,7,23]],"date-time":"2022-07-23T00:00:00Z","timestamp":1658534400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004063","name":"Knut och Alice Wallenbergs Stiftelse","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004063","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006313","name":"Barncancerfonden","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006313","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002794","name":"Cancerfonden","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002794","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001722","name":"Koninklijke Nederlandse Akademie van Wetenschappen","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001722","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004047","name":"Karolinska Institutet","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004047","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004047","name":"Karolinska Institute","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004047","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Clin Immunol"],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:title>Abstract\n<\/jats:title><jats:p>Autosomal recessive mutations in <jats:italic>RAB27A<\/jats:italic> are associated with Griscelli syndrome type 2 (GS2), characterized by hypopigmentation and development of early-onset, potentially fatal hemophagocytic lymphohistiocytosis (HLH). We describe a 35-year old male who presented with recurrent fever, was diagnosed with Epstein-Barr virus-driven chronic lymphoproliferation, fulfilled clinical HLH criteria, and who carried a novel homozygous <jats:italic>RAB27A<\/jats:italic> c.551G\u2009&gt;\u2009A p.(R184Q) variant. We aimed to evaluate the contribution of the identified <jats:italic>RAB27A<\/jats:italic> variant in regard to the clinical phenotype as well as cellular and biochemical function. The patient displayed normal pigmentation as well as RAB27A expression in blood-derived cells. However, patient NK and CD8<jats:sup>+<\/jats:sup> T cell exocytosis was low. Ectopic expression of the RAB27A p.R184Q variant rescued melanosome distribution in mouse Rab27a-deficient melanocytes, but failed to increase exocytosis upon reconstitution of human RAB27A-deficient CD8<jats:sup>+<\/jats:sup> T cells. Mechanistically, the RAB27A p.R184Q variant displayed reduced binding to SLP2A but augmented binding to MUNC13-4, two key effector proteins in immune cells. MUNC13-4 binding was particularly strong to an inactive RAB27A p.T23N\/p.R184Q double mutant. RAB27A p.R184Q was expressed and could facilitate melanosome trafficking, but did not support lymphocyte exocytosis. The HLH-associated RAB27A variant increased Munc13-4 binding, potentially representing a novel mode of impairing RAB27A function selectively in hematopoietic cells.<\/jats:p>","DOI":"10.1007\/s10875-022-01315-4","type":"journal-article","created":{"date-parts":[[2022,7,23]],"date-time":"2022-07-23T05:04:08Z","timestamp":1658552648000},"page":"1685-1695","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Novel RAB27A Variant Associated with Late-Onset Hemophagocytic Lymphohistiocytosis Alters Effector Protein Binding"],"prefix":"10.1007","volume":"42","author":[{"given":"Timo C. E.","family":"Zondag","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lamberto","family":"Torralba-Raga","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan A. M.","family":"Van Laar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maud A. W.","family":"Hermans","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arjen","family":"Bouman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iris H. I. M.","family":"Hollink","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P. Martin","family":"Van Hagen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deborah A.","family":"Briggs","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alistair N.","family":"Hume","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yenan T.","family":"Bryceson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,7,23]]},"reference":[{"key":"1315_CR1","doi-asserted-by":"publisher","first-page":"3495","DOI":"10.1038\/s41467-020-17212-6","volume":"11","author":"N Alzahofi","year":"2020","unstructured":"Alzahofi N, Welz T, Robinson CL, Page EL, Briggs DA, Stainthorp AK, Reekes J, Elbe DA, Straub F, Kallemeijn WW, Tate EW, Goff PS, Sviderskaya EV, Cantero M, Montoliu L, Nedelec F, Miles AK, Bailly M, Kerkhoff E, Hume AN. Rab27a co-ordinates actin-dependent transport by controlling organelle-associated motors and track assembly proteins. Nat Commun. 2020;11:3495.","journal-title":"Nat Commun"},{"key":"1315_CR2","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1038\/366643a0","volume":"366","author":"MS Boguski","year":"1993","unstructured":"Boguski MS, McCormick F. Proteins regulating Ras and its relatives. Nature. 1993;366:643\u201354.","journal-title":"Nature"},{"key":"1315_CR3","doi-asserted-by":"publisher","first-page":"2754","DOI":"10.1182\/blood-2011-08-374199","volume":"119","author":"YT Bryceson","year":"2012","unstructured":"Bryceson YT, Pende D, Maul-Pavicic A, Gilmour KC, Ufheil H, Vraetz T, Chiang SC, Marcenaro S, Meazza R, Bondzio I, Walshe D, Janka G, Lehmberg K, Beutel K, zur Stadt U, Binder N, Arico M, Moretta L, Henter JI, Ehl S. A prospective evaluation of degranulation assays in the rapid diagnosis of familial hemophagocytic syndromes. Blood. 2012;119:2754\u201363.","journal-title":"Blood"},{"issue":"1310\u20131318","key":"1315_CR4","first-page":"e1311","volume":"135","author":"V Cetica","year":"2015","unstructured":"Cetica V, Hackmann Y, Grieve S, Sieni E, Ciambotti B, Coniglio ML, Pende D, Gilmour K, Romagnoli P, Griffiths GM, Arico M. Patients with Griscelli syndrome and normal pigmentation identify RAB27A mutations that selectively disrupt MUNC13-4 binding. J Allergy Clin Immunol. 2015;135(1310\u20131318):e1311.","journal-title":"J Allergy Clin Immunol"},{"key":"1315_CR5","doi-asserted-by":"publisher","first-page":"1468","DOI":"10.1016\/j.str.2008.07.015","volume":"16","author":"LM Chavas","year":"2008","unstructured":"Chavas LM, Ihara K, Kawasaki M, Torii S, Uejima T, Kato R, Izumi T, Wakatsuki S. Elucidation of Rab27 recruitment by its effectors: structure of Rab27a bound to Exophilin4\/Slp2-a. Structure. 2008;16:1468\u201377.","journal-title":"Structure"},{"key":"1315_CR6","doi-asserted-by":"publisher","first-page":"9809","DOI":"10.1073\/pnas.0903815106","volume":"106","author":"J Chia","year":"2009","unstructured":"Chia J, Yeo KP, Whisstock JC, Dunstone MA, Trapani JA, Voskoboinik I. Temperature sensitivity of human perforin mutants unmasks subtotal loss of cytotoxicity, delayed FHL, and a predisposition to cancer. Proc Natl Acad Sci USA. 2009;106:9809\u201314.","journal-title":"Proc Natl Acad Sci USA"},{"key":"1315_CR7","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1182\/blood-2012-07-442558","volume":"121","author":"SC Chiang","year":"2013","unstructured":"Chiang SC, Theorell J, Entesarian M, Meeths M, Mastafa M, Al-Herz W, Frisk P, Gilmour KC, Ifversen M, Langenski\u00f6ld C, Machaczka M, Naqvi A, Payne J, Perez-Martinez A, Sabel M, Unal E, Unal S, Winiarski J, Nordenskj\u00f6ld M, Ljunggren HG, Henter JI, Bryceson YT. Comparison of primary human cytotoxic T-cell and natural killer cell responses reveal similar molecular requirements for lytic granule exocytosis but differences in cytokine production. Blood. 2013;121:1345\u201356.","journal-title":"Blood"},{"key":"1315_CR8","doi-asserted-by":"publisher","first-page":"568","DOI":"10.1038\/nri2803","volume":"10","author":"G de Saint Basile","year":"2010","unstructured":"de Saint Basile G, M\u00e9nasch\u00e9 G, Fischer A. Molecular mechanisms of biogenesis and exocytosis of cytotoxic granules. Nat Rev Immunol. 2010;10:568\u201379.","journal-title":"Nat Rev Immunol"},{"key":"1315_CR9","doi-asserted-by":"publisher","first-page":"1570","DOI":"10.1182\/blood-2011-02-339523","volume":"118","author":"ED Elstak","year":"2011","unstructured":"Elstak ED, Neeft M, Nehme NT, Voortman J, Cheung M, Goodarzifard M, Gerritsen HC, van Bergen En PM, Henegouwen I, de Callebaut G, Basile S, van der Sluijs P. The munc13-4-rab27 complex is specifically required for tethering secretory lysosomes at the plasma membrane. Blood. 2011;118:1570\u20138.","journal-title":"Blood"},{"key":"1315_CR10","doi-asserted-by":"publisher","first-page":"835","DOI":"10.1083\/jcb.152.4.835","volume":"152","author":"EK Haddad","year":"2001","unstructured":"Haddad EK, Wu X, Hammer JA 3rd, Henkart PA. Defective granule exocytosis in Rab27a-deficient lymphocytes from ashen mice. J Cell Biol. 2001;152:835\u201342.","journal-title":"J Cell Biol"},{"key":"1315_CR11","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1002\/pbc.21039","volume":"48","author":"JI Henter","year":"2007","unstructured":"Henter JI, Horne A, Aric\u00f3 M, Egeler RM, Filipovich AH, Imashuku S, Ladisch S, McClain K, Webb D, Winiarski J, Janka G. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48:124\u201331.","journal-title":"Pediatr Blood Cancer"},{"key":"1315_CR12","doi-asserted-by":"publisher","first-page":"446","DOI":"10.1111\/j.1600-0854.2008.00714.x","volume":"9","author":"O Holt","year":"2008","unstructured":"Holt O, Kanno E, Bossi G, Booth S, Daniele T, Santoro A, Arico M, Saegusa C, Fukuda M, Griffiths GM. Slp1 and Slp2-a localize to the plasma membrane of CTL and contribute to secretion from the immunological synapse. Traffic. 2008;9:446\u201357.","journal-title":"Traffic"},{"key":"1315_CR13","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1034\/j.1600-0854.2002.030305.x","volume":"3","author":"AN Hume","year":"2002","unstructured":"Hume AN, Collinson LM, Hopkins CR, Strom M, Barral DC, Bossi G, Griffiths GM, Seabra MC. The leaden gene product is required with Rab27a to recruit myosin Va to melanosomes in melanocytes. Traffic. 2002;3:193\u2013202.","journal-title":"Traffic"},{"key":"1315_CR14","doi-asserted-by":"publisher","first-page":"4720","DOI":"10.1091\/mbc.e06-05-0457","volume":"17","author":"AN Hume","year":"2006","unstructured":"Hume AN, Tarafder AK, Ramalho JS, Sviderskaya EV, Seabra MC. A coiled-coil domain of melanophilin is essential for Myosin Va recruitment and melanosome transport in melanocytes. Mol Biol Cell. 2006;17:4720\u201335.","journal-title":"Mol Biol Cell"},{"key":"1315_CR15","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","volume":"581","author":"KJ Karczewski","year":"2020","unstructured":"Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alf\u00f6ldi J, Wang Q, Collins RL, Laricchia KM, Ganna A, Birnbaum DP, Gauthier LD, Brand H, Solomonson M, Watts NA, Rhodes D, Singer-Berk M, England EM, Seaby EG, Kosmicki JA, Walters RK, Tashman K, Farjoun Y, Banks E, Poterba T, Wang A, Seed C, Whiffin N, Chong JX, Samocha KE, Pierce-Hoffman E, Zappala Z, Odonnell-Luria AH, Minikel EV, Weisburd B, Lek M, Ware JS, Vittal C, Armean IM, Bergelson L, Cibulskis K, Connolly KM, Covarrubias M, Donnelly S, Ferriera S, Gabriel S, Gentry J, Gupta N, Jeandet T, Kaplan D, Llanwarne C, Munshi R, Novod S, Petrillo N, Roazen D, Ruano-Rubio V, Saltzman A, Schleicher M, Soto J, Tibbetts K, Tolonen C, Wade G, Talkowski ME, Genome Aggregation Database Consortium; BM Neale, Daly MJ, MacArthur DG. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581:434\u201343.","journal-title":"Nature"},{"key":"1315_CR16","doi-asserted-by":"publisher","first-page":"310","DOI":"10.1038\/ng.2892","volume":"46","author":"M Kircher","year":"2014","unstructured":"Kircher M, Witten DM, Jain P, O\u2019Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014;46:310\u20135.","journal-title":"Nat Genet"},{"key":"1315_CR17","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1002\/1096-8628(20010801)102:2<125::AID-AJMG1439>3.0.CO;2-0","volume":"102","author":"S Kivitie-Kallio","year":"2001","unstructured":"Kivitie-Kallio S, Norio R. Cohen syndrome: essential features, natural history, and heterogeneity. Am J Med Genet. 2001;102:125\u201335.","journal-title":"Am J Med Genet"},{"key":"1315_CR18","doi-asserted-by":"publisher","first-page":"886","DOI":"10.1016\/S0022-3476(05)82003-7","volume":"125","author":"C Klein","year":"1994","unstructured":"Klein C, Philippe N, Le Deist F, Fraitag S, Prost C, Durandy A, Fischer A, Griscelli C. Partial albinism with immunodeficiency (Griscelli syndrome). J Pediatr. 1994;125:886\u201395.","journal-title":"J Pediatr"},{"key":"1315_CR19","doi-asserted-by":"publisher","first-page":"1359","DOI":"10.1086\/375454","volume":"72","author":"J Kolehmainen","year":"2003","unstructured":"Kolehmainen J, Black GC, Saarinen A, Chandler K, Clayton-Smith J, Traskelin AL, Perveen R, Kivitie-Kallio S, Norio R, Warburg M, Fryns JP, de la Chapelle A, Lehesjoki AE. Cohen syndrome is caused by mutations in a novel gene, COH1, encoding a transmembrane protein with a presumed role in vesicle-mediated sorting and intracellular protein transport. Am J Hum Genet. 2003;72:1359\u201369.","journal-title":"Am J Hum Genet"},{"key":"1315_CR20","doi-asserted-by":"publisher","first-page":"1478","DOI":"10.1016\/j.str.2008.07.014","volume":"16","author":"M Kukimoto-Niino","year":"2008","unstructured":"Kukimoto-Niino M, Sakamoto A, Kanno E, Hanawa-Suetsugu K, Terada T, Shirouzu M, Fukuda M, Yokoyama S. Structural basis for the exclusive specificity of Slac2-a\/melanophilin for the Rab27 GTPases. Structure. 2008;16:1478\u201390.","journal-title":"Structure"},{"key":"1315_CR21","doi-asserted-by":"publisher","first-page":"46798","DOI":"10.1074\/jbc.M307799200","volume":"278","author":"B Larijani","year":"2003","unstructured":"Larijani B, Hume AN, Tarafder AK, Seabra MC. Multiple factors contribute to inefficient prenylation of Rab27a in Rab prenylation diseases. J Biol Chem. 2003;278:46798\u2013804.","journal-title":"J Biol Chem"},{"key":"1315_CR22","doi-asserted-by":"publisher","first-page":"1661","DOI":"10.1016\/j.jaci.2019.03.009","volume":"143","author":"HY Lu","year":"2019","unstructured":"Lu HY, Biggs CM, Blanchard-Rohner G, Fung SY, Sharma M, Turvey SE. Germline CBM-opathies: from immunodeficiency to atopy. J Allergy Clin Immunol. 2019;143:1661\u201373.","journal-title":"J Allergy Clin Immunol"},{"key":"1315_CR23","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1038\/ni1431","volume":"8","author":"MM Menager","year":"2007","unstructured":"Menager MM, Menasche G, Romao M, Knapnougel P, Ho CH, Garfa M, Raposo G, Feldmann J, Fischer A, de Saint Basile G. Secretory cytotoxic granule maturation and exocytosis require the effector protein hMunc13-4. Nat Immunol. 2007;8:257\u201367.","journal-title":"Nat Immunol"},{"key":"1315_CR24","doi-asserted-by":"publisher","first-page":"2736","DOI":"10.1182\/blood-2002-09-2789","volume":"101","author":"G Menasche","year":"2003","unstructured":"Menasche G, Feldmann J, Houdusse A, Desaymard C, Fischer A, Goud B, de Saint Basile G. Biochemical and functional characterization of Rab27a mutations occurring in Griscelli syndrome patients. Blood. 2003;101:2736\u201342.","journal-title":"Blood"},{"key":"1315_CR25","doi-asserted-by":"publisher","first-page":"5052","DOI":"10.1182\/blood-2008-02-141069","volume":"112","author":"G Menasche","year":"2008","unstructured":"Menasche G, Menager MM, Lefebvre JM, Deutsch E, Athman R, Lambert N, Mahlaoui N, Court M, Garin J, Fischer A, de Saint Basile G. A newly identified isoform of Slp2a associates with Rab27a in cytotoxic T cells and participates to cytotoxic granule secretion. Blood. 2008;112:5052\u201362.","journal-title":"Blood"},{"key":"1315_CR26","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1038\/76024","volume":"25","author":"G M\u00e9nasch\u00e9","year":"2000","unstructured":"M\u00e9nasch\u00e9 G, Pastural E, Feldmann J, Certain S, Ersoy F, Dupuis S, Wulffraat N, Bianchi D, Fischer A, Le Deist F, de Saint Basile G. Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome. Nat Genet. 2000;25:173\u20136.","journal-title":"Nat Genet"},{"key":"1315_CR27","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1590\/S0100-879X2008001000002","volume":"41","author":"IP Meschede","year":"2008","unstructured":"Meschede IP, Santos TO, Izidoro-Toledo TC, Gurgel-Gianetti J, Espreafico EM. Griscelli syndrome-type 2 in twin siblings: case report and update on RAB27A human mutations and gene structure. Braz J Med Biol Res Revista Brasileira De Pesquisas Medicas E Biologicas. 2008;41:839\u201348.","journal-title":"Braz J Med Biol Res Revista Brasileira De Pesquisas Medicas E Biologicas"},{"key":"1315_CR28","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/0014-5793(90)81431-M","volume":"275","author":"K Nagata","year":"1990","unstructured":"Nagata K, Satoh T, Itoh H, Kozasa T, Okano Y, Doi T, Kaziro Y, Nozawa Y. The ram: a novel low molecular weight GTP-binding protein cDNA from a rat megakaryocyte library. FEBS Lett. 1990;275:29\u201332.","journal-title":"FEBS Lett"},{"issue":"599\u2013601","key":"1315_CR29","first-page":"e593","volume":"138","author":"P Netter","year":"2016","unstructured":"Netter P, Chan SK, Banerjee PP, Monaco-Shawver L, Noroski LM, Hanson IC, Forbes LR, Mace EM, Chinen J, Gaspar HB, Sleiman P, Hakonarson H, Klein C, Ehlayel MS, Orange JS. A novel Rab27a mutation binds melanophilin, but not Munc13-4, causing immunodeficiency without albinism. J Allergy Clin Immunol. 2016;138(599\u2013601):e593.","journal-title":"J Allergy Clin Immunol"},{"key":"1315_CR30","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/j.1399-0004.1984.tb00456.x","volume":"25","author":"R Norio","year":"1984","unstructured":"Norio R, Raitta C, Lindahl E. Further delineation of the Cohen syndrome; report on chorioretinal dystrophy, leukopenia and consanguinity. Clin Genet. 1984;25:1\u201314.","journal-title":"Clin Genet"},{"key":"1315_CR31","doi-asserted-by":"publisher","first-page":"612977","DOI":"10.3389\/fimmu.2020.612977","volume":"11","author":"Y Ohishi","year":"2020","unstructured":"Ohishi Y, Ammann S, Ziaee V, Strege K, Gro\u00df M, Amos CV, Shahrooei M, Ashournia P, Razaghian A, Griffiths GM, Ehl S, Fukuda M, Parvaneh N. Griscelli syndrome type 2 sine albinism: unraveling differential RAB27A effector engagement. Front Immunol. 2020;11:612977.","journal-title":"Front Immunol"},{"key":"1315_CR32","first-page":"67","volume":"27","author":"T Patiroglu","year":"2016","unstructured":"Patiroglu T, Akar HH, Unal E, Chiang SC, Schlums H, Tesi B, Ozkars MY, Karakukcu M. Partial oculocutaneous albinism and immunodeficiency syndromes: ten years experience from a single center in Turkey. Genet Couns (Geneva, Switzerland). 2016;27:67\u201376.","journal-title":"Genet Couns (Geneva, Switzerland)"},{"key":"1315_CR33","doi-asserted-by":"publisher","first-page":"1077","DOI":"10.1006\/jmbi.2000.4010","volume":"301","author":"JB Pereira-Leal","year":"2000","unstructured":"Pereira-Leal JB, Seabra MC. The mammalian Rab family of small GTPases: definition of family and subfamily sequence motifs suggests a mechanism for functional specificity in the Ras superfamily. J Mol Biol. 2000;301:1077\u201387.","journal-title":"J Mol Biol"},{"key":"1315_CR34","doi-asserted-by":"publisher","first-page":"749","DOI":"10.1016\/j.cell.2004.05.017","volume":"117","author":"A Rak","year":"2004","unstructured":"Rak A, Pylypenko O, Niculae A, Pyatkov K, Goody RS, Alexandrov K. Structure of the Rab7:REP-1 complex: insights into the mechanism of Rab prenylation and choroideremia disease. Cell. 2004;117:749\u201360.","journal-title":"Cell"},{"key":"1315_CR35","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1186\/s13073-021-00835-9","volume":"13","author":"P Rentzsch","year":"2021","unstructured":"Rentzsch P, Schubach M, Shendure J, Kircher M. CADD-splice-improving genome-wide variant effect prediction using deep learning-derived splice scores. Genome Med. 2021;13:31.","journal-title":"Genome Med"},{"key":"1315_CR36","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1136\/jmg.2007.054288","volume":"45","author":"E Rudd","year":"2008","unstructured":"Rudd E, Bryceson YT, Zheng C, Edner J, Wood SM, Ramme K, Gavhed S, G\u00fcrgey A, Hellebostad M, Bechensteen AG, Ljunggren HG, Fadeel B, Nordenskj\u00f6ld M, Henter JI. Spectrum, and clinical and functional implications of UNC13D mutations in familial haemophagocytic lymphohistiocytosis. J Med Genet. 2008;45:134\u201341.","journal-title":"J Med Genet"},{"key":"1315_CR37","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1182\/blood-2012-07-440339","volume":"121","author":"FE Sepulveda","year":"2013","unstructured":"Sepulveda FE, Debeurme F, Menasche G, Kurowska M, Cote M, PachlopnikSchmid J, Fischer A, de Saint Basile G. Distinct severity of HLH in both human and murine mutants with complete loss of cytotoxic effector PRF1, RAB27A, and STX11. Blood. 2013;121:595\u2013603.","journal-title":"Blood"},{"key":"1315_CR38","doi-asserted-by":"publisher","first-page":"10730","DOI":"10.1074\/jbc.M309426200","volume":"279","author":"R Shirakawa","year":"2004","unstructured":"Shirakawa R, Higashi T, Tabuchi A, Yoshioka A, Nishioka H, Fukuda M, Kita T, Horiuchi H. Munc13-4 is a GTP-Rab27-binding protein regulating dense core granule secretion in platelets. J Biol Chem. 2004;279:10730\u20137.","journal-title":"J Biol Chem"},{"issue":"317\u2013321","key":"1315_CR39","first-page":"e318","volume":"142","author":"B Tesi","year":"2018","unstructured":"Tesi B, Rascon J, Chiang SCC, Burnyte B, Lofstedt A, Fasth A, Heizmann M, Juozapaite S, Kiudeliene R, Kvedaraite E, Miseviciene V, Muleviciene A, Muller ML, Nordenskjold M, Matuzeviciene R, Samaitiene R, Speckmann C, Stankeviciene S, Zekas V, Voss M, Ehl S, Vaiciene-Magistris N, Henter JI, Meeths M, Bryceson YT. A RAB27A 5\u2019 untranslated region structural variant associated with late-onset hemophagocytic lymphohistiocytosis and normal pigmentation. J Allergy Clin Immunol. 2018;142(317\u2013321):e318.","journal-title":"J Allergy Clin Immunol"},{"key":"1315_CR40","doi-asserted-by":"publisher","first-page":"268","DOI":"10.1111\/j.1755-148X.2009.00558.x","volume":"22","author":"M Van Gele","year":"2009","unstructured":"Van Gele M, Dynoodt P, Lambert J. Griscelli syndrome: a model system to study vesicular trafficking. Pigment Cell Melanoma Res. 2009;22:268\u201382.","journal-title":"Pigment Cell Melanoma Res"},{"key":"1315_CR41","doi-asserted-by":"publisher","first-page":"7933","DOI":"10.1073\/pnas.140212797","volume":"97","author":"SM Wilson","year":"2000","unstructured":"Wilson SM, Yip R, Swing DA, O\u2019Sullivan TN, Zhang Y, Novak EK, Swank RT, Russell LB, Copeland NG, Jenkins NA. A mutation in Rab27a causes the vesicle transport defects observed in ashen mice. Proc Natl Acad Sci USA. 2000;97:7933\u20138.","journal-title":"Proc Natl Acad Sci USA"}],"container-title":["Journal of Clinical Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10875-022-01315-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10875-022-01315-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10875-022-01315-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,25]],"date-time":"2022-11-25T22:42:49Z","timestamp":1669416169000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10875-022-01315-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,23]]},"references-count":41,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2022,11]]}},"alternative-id":["1315"],"URL":"https:\/\/doi.org\/10.1007\/s10875-022-01315-4","relation":{},"ISSN":["0271-9142","1573-2592"],"issn-type":[{"value":"0271-9142","type":"print"},{"value":"1573-2592","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,23]]},"assertion":[{"value":"1 November 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 June 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 July 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study was approved by the ethics committees of the Board of Stockholm.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics Approval"}},{"value":"Informed written consents from the individuals included in the study were obtained according to the Declaration of Helsinki.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to Participate"}},{"value":"The patient consented to present data in a medical journal.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for Publication"}},{"value":"The authors declare no competing interests.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of Interest"}}]}}