Founder effects in two predominant intronic mutations of UNC13D, c.118-308C>T and c.754-1G>C underlie the unusual predominance of type 3 familial hemophagocytic lymphohistiocytosis (FHL3) in Korea
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  • 作者:Ja Young Seo (1)
    Joon-Sup Song (3)
    Ki-O Lee (4)
    Hong-Hee Won (4)
    Jong-Won Kim (1)
    Sun-Hee Kim (1)
    Soo-Hyun Lee (5)
    Keon-Hee Yoo (5)
    Ki-Woong Sung (5)
    Hong Hoe Koo (5)
    Hyoung Jin Kang (6)
    Hee Young Shin (6)
    Hyo-Seop Ahn (6)
    Dong Kyun Han (7)
    Hoon Kook (7)
    Tai Ju Hwang (7)
    Chuhl-Joo Lyu (8)
    Mi-Jung Lee (9)
    Ji-Yoon Kim (10)
    Sung-Shik Park (11)
    Young-Tak Lim (12)
    Bo-Eun Kim (13)
    Kyung-Nam Koh (13)
    Ho Joon Im (13)
    Jong Jin Seo (13)
    Hee-Jin Kim (1) (2)
  • 关键词:Hemophagocytic lymphohistiocytosis ; Familial ; FHL3 ; UNC13D ; Founder effect ; Korea
  • 刊名:Annals of Hematology
  • 出版年:2013
  • 出版时间:March 2013
  • 年:2013
  • 卷:92
  • 期:3
  • 页码:357-364
  • 全文大小:212KB
  • 参考文献:1. Henter JI, Arico M, Elinder G, Imashuku S, Janka G (1998) Familial hemophagocytic lymphohistiocytosis. Primary hemophagocytic lymphohistiocytosis. Hematol Oncol Clin North Am 12:417-33 f="http://dx.doi.org/10.1016/S0889-8588(05)70520-7">CrossRef
    2. Janka GE (2005) Hemophagocytic lymphohistiocytosis. Hematology 10(Suppl 1):104-07 f="http://dx.doi.org/10.1080/10245330512331390087">CrossRef
    3. Henter JI, Horne A, Arico M, Egeler RM, Filipovich AH, Imashuku S, Ladisch S, McClain K, Webb D, Winiarski J, Janka G (2007) HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 48:124-31 f="http://dx.doi.org/10.1002/pbc.21039">CrossRef
    4. Henter JI, Samuelsson-Horne A, Arico M, Egeler RM, Elinder G, Filipovich AH, Gadner H, Imashuku S, Komp D, Ladisch S, Webb D, Janka G (2002) Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation. Blood 100:2367-373 f="http://dx.doi.org/10.1182/blood-2002-01-0172">CrossRef
    5. Sung L, King SM, Carcao M, Trebo M, Weitzman SS (2002) Adverse outcomes in primary hemophagocytic lymphohistiocytosis. J Pediatr Hematol Oncol 24:550-54 f="http://dx.doi.org/10.1097/00043426-200210000-00011">CrossRef
    6. Stepp SE, Dufourcq-Lagelouse R, Le Deist F, Bhawan S, Certain S, Mathew PA, Henter JI, Bennett M, Fischer A, de Saint BG, Kumar V (1999) Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science 286:1957-959 f="http://dx.doi.org/10.1126/science.286.5446.1957">CrossRef
    7. Feldmann J, Callebaut I, Raposo G, Certain S, Bacq D, Dumont C, Lambert N, Ouachee-Chardin M, Chedeville G, Tamary H, Minard-Colin V, Vilmer E, Blanche S, Le Deist F, Fischer A, de Saint BG (2003) Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3). Cell 115:461-73 f="http://dx.doi.org/10.1016/S0092-8674(03)00855-9">CrossRef
    8. zur Stadt U, Schmidt S, Kasper B, Beutel K, Diler AS, Henter JI, Kabisch H, Schneppenheim R, Nurnberg P, Janka G, Hennies HC (2005) Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11. Hum Mol Genet 14:827-34 f="http://dx.doi.org/10.1093/hmg/ddi076">CrossRef
    9. zur Stadt U, Hennies HC, Rohr J, Seifert W, Koch F, Grieve S, Pagel J, Strauss J, Kasper B, Nurnberg G, Becker C, Maul-Pavicic A, Beutel K, Janka G, Griffiths G, Ehl S (2009) Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11. Am J Hum Genet 85:482-92 f="http://dx.doi.org/10.1016/j.ajhg.2009.09.005">CrossRef
    10. Goransdotter Ericson K, Fadeel B, Nilsson-Ardnor S, Soderhall C, Samuelsson A, Janka G, Schneider M, Gurgey A, Yalman N, Revesz T, Egeler R, Jahnukainen K, Storm-Mathiesen I, Haraldsson A, Poole J, de Saint Basile G, Nordenskjold M, Henter J (2001) Spectrum of perforin gene mutations in familial hemophagocytic lymphohistiocytosis. Am J Hum Genet 68:590-97 f="http://dx.doi.org/10.1086/318796">CrossRef
    11. Molleran Lee S, Villanueva J, Sumegi J, Zhang K, Kogawa K, Davis J, Filipovich AH (2004) Characterisation of diverse PRF1 mutations leading to decreased natural killer cell activity in North American families with haemophagocytic lymphohistiocytosis. J Med Genet 41:137-44 f="http://dx.doi.org/10.1136/jmg.2003.011528">CrossRef
    12. Zur Stadt U, Beutel K, Kolberg S, Schneppenheim R, Kabisch H, Janka G, Hennies HC (2006) Mutation spectrum in children with primary hemophagocytic lymphohistiocytosis: molecular and functional analyses of PRF1, UNC13D, STX11, and RAB27A. Hum Mutat 27:62-8 f="http://dx.doi.org/10.1002/humu.20274">CrossRef
    13. Santoro A, Cannella S, Bossi G, Gallo F, Trizzino A, Pende D, Dieli F, Bruno G, Stinchcombe JC, Micalizzi C, De Fusco C, Danesino C, Moretta L, Notarangelo LD, Griffiths GM, Aricò M (2006) Novel Munc13-4 mutations in children and young adult patients with haemophagocytic lymphohistiocytosis. J Med Genet 43:953-60 f="http://dx.doi.org/10.1136/jmg.2006.041863">CrossRef
    14. Horne A, Ramme KG, Rudd E, Zheng C, Wali Y, al-Lamki Z, Gurgey A, Yalman N, Nordenskjold M, Henter JI (2008) Characterization of PRF1, STX11 and UNC13D genotype–phenotype correlations in familial hemophagocytic lymphohistiocytosis. Br J Haematol 143:75-3 f="http://dx.doi.org/10.1111/j.1365-2141.2008.07315.x">CrossRef
    15. Lee SM, Sumegi J, Villanueva J, Tabata Y, Zhang K, Chakraborty R, Sheng X, Clementi R, de Saint Basile G, Filipovich AH (2006) Patients of African ancestry with hemophagocytic lymphohistiocytosis share a common haplotype of PRF1 with a 50delT mutation. J Pediatr 149:134-37 f="http://dx.doi.org/10.1016/j.jpeds.2006.03.003">CrossRef
    16. Ishii E, Ueda I, Shirakawa R, Yamamoto K, Horiuchi H, Ohga S, Furuno K, Morimoto A, Imayoshi M, Ogata Y, Zaitsu M, Sako M, Koike K, Sakata A, Takada H, Hara T, Imashuku S, Sasazuki T, Yasukawa M (2005) Genetic subtypes of familial hemophagocytic lymphohistiocytosis: correlations with clinical features and cytotoxic T lymphocyte/natural killer cell functions. Blood 105:3442-448 f="http://dx.doi.org/10.1182/blood-2004-08-3296">CrossRef
    17. Yoon HS, Kim HJ, Yoo KH, Sung KW, Koo HH, Kang HJ, Shin HY, Ahn HS, Kim JY, Lim YT, Bae KW, Lee KO, Shin JS, Lee ST, Chung HS, Kim SH, Park CJ, Chi HS, Im HJ, Seo JJ (2010) UNC13D is the predominant causative gene with recurrent splicing mutations in Korean patients with familial hemophagocytic lymphohistiocytosis. Haematologica 95:622-26 f="http://dx.doi.org/10.3324/haematol.2009.016949">CrossRef
    18. Meeths M, Chiang SC, Wood SM, Entesarian M, Schlums H, Bang B, Nordenskjold E, Bjorklund C, Jakovljevic G, Jazbec J, Hasle H, Holmqvist BM, Rajic L, Pfeifer S, Rosthoj S, Sabel M, Salmi TT, Stokland T, Winiarski J, Ljunggren HG, Fadeel B, Nordenskjold M, Henter JI, Bryceson YT (2011) Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) caused by deep intronic mutation and inversion in UNC13D. Blood 118(22):5783-3 f="http://dx.doi.org/10.1182/blood-2011-07-369090">CrossRef
    19. Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263-65 f="http://dx.doi.org/10.1093/bioinformatics/bth457">CrossRef
    20. Wall JD, Pritchard JK (2003) Haplotype blocks and linkage disequilibrium in the human genome. Nat Rev Genet 4:587-97 f="http://dx.doi.org/10.1038/nrg1123">CrossRef
    21. Stephens M, Smith NJ, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68:978-89 f="http://dx.doi.org/10.1086/319501">CrossRef
    22. Santoro A, Cannella S, Trizzino A, Bruno G, De Fusco C, Notarangelo LD, Pende D, Griffiths GM, Aricò M (2008) Mutations affecting mRNA splicing are the most common molecular defect in patients with familial hemophagocytic lymphohistiocytosis type 3. Haematologica 93:1086-090 f="http://dx.doi.org/10.3324/haematol.12622">CrossRef
    23. Sieni E, Cetica V, Santoro A, Beutel K, Mastrodicasa E, Meeths M, Ciambotti B, Brugnolo F, zur Stadt U, Pende D, Moretta L, Griffiths GM, Henter JI, Janka G, Arico M (2011) Genotype-phenotype study of familial haemophagocytic lymphohistiocytosis type 3. J Med Genet 48:343-52 f="http://dx.doi.org/10.1136/jmg.2010.085456">CrossRef
    24. Ueda I, Morimoto A, Inaba T, Yagi T, Hibi S, Sugimoto T, Sako M, Yanai F, Fukushima T, Nakayama M, Ishii E, Imashuku S (2003) Characteristic perforin gene mutations of haemophagocytic lymphohistiocytosis patients in Japan. Br J Haematol 121:503-10 f="http://dx.doi.org/10.1046/j.1365-2141.2003.04298.x">CrossRef
    25. Clementi R, zur Stadt U, Savoldi G, Varoitto S, Conter V, De Fusco C, Notarangelo LD, Schneider M, Klersy C, Janka G, Danesino C, Arico M (2001) Six novel mutations in the PRF1 gene in children with haemophagocytic lymphohistiocytosis. J Med Genet 38:643-46 f="http://dx.doi.org/10.1136/jmg.38.9.643">CrossRef
    26. Zhang K, Jordan MB, Marsh RA, Johnson JA, Kissell D, Meller J, Villanueva J, Risma KA, Wei Q, Klein PS, Filipovich AH (2011) Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH. Blood 118:5794-798 f="http://dx.doi.org/10.1182/blood-2011-07-370148">CrossRef
    27. Olcaydu D, Harutyunyan A, Jager R, Berg T, Gisslinger B, Pabinger I, Gisslinger H, Kralovics R (2009) A common JAK2 haplotype confers susceptibility to myeloproliferative neoplasms. Nat Genet 41:450-54 f="http://dx.doi.org/10.1038/ng.341">CrossRef
  • 作者单位:Ja Young Seo (1)
    Joon-Sup Song (3)
    Ki-O Lee (4)
    Hong-Hee Won (4)
    Jong-Won Kim (1)
    Sun-Hee Kim (1)
    Soo-Hyun Lee (5)
    Keon-Hee Yoo (5)
    Ki-Woong Sung (5)
    Hong Hoe Koo (5)
    Hyoung Jin Kang (6)
    Hee Young Shin (6)
    Hyo-Seop Ahn (6)
    Dong Kyun Han (7)
    Hoon Kook (7)
    Tai Ju Hwang (7)
    Chuhl-Joo Lyu (8)
    Mi-Jung Lee (9)
    Ji-Yoon Kim (10)
    Sung-Shik Park (11)
    Young-Tak Lim (12)
    Bo-Eun Kim (13)
    Kyung-Nam Koh (13)
    Ho Joon Im (13)
    Jong Jin Seo (13)
    Hee-Jin Kim (1) (2)

    1. Department of Laboratory Medicine & Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul, 135-710, South Korea
    3. Department of Pediatrics, Kangdong Sacred Heart Hospital, University of Hallym College of Medicine, Seoul, South Korea
    4. Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, South Korea
    5. Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
    6. Department of Pediatrics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
    7. Department of Pediatrics, Chonnam National University Hwasun Hospital, Chonnam, South Korea
    8. Department of Pediatrics, Yonsei University Severance Hospital, Seoul, South Korea
    9. Department of Pediatrics, Dankook University Hospital, Cheonan, South Korea
    10. Department of Pediatrics, Chungbuk National University Hospital, Cheongjoo, South Korea
    11. Department of Pediatrics, Pusan National University Yangsan Hospital, Yangsan, South Korea
    12. Department of Pediatrics, Pusan National University Hospital, Pusan, South Korea
    13. Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap-2-dong, Songpa-gu, Seoul, 138-736, South Korea
    2. Cardiac & Vascular Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
  • ISSN:1432-0584
文摘
Familial hemophagocytic lymphohistiocytosis (familial HLH or FHL) is a potentially fatal autosomal recessive disorder. Our previous study demonstrated that UNC13D mutations (FHL3) account for ?0?% of FHL in Korea with recurrent splicing mutation c.754-1G>C (IVS9-1G>C). Notably, half of the FHL3 patients had a monoallelic mutation of UNC13D. Deep intronic mutations in UNC13D were recently reported in patients of European descent. In this study, we performed targeted mutation analyses for deep intronic mutations and investigated on the founder effect in FHL3 in Korean patients. The study patients were 72 children with HLH including those with FHL3 previously reported to have a monoallelic UNC13D mutation. All patients were recruited from the Korean Registry of Hemophagocytic Lymphohistiocytosis. In addition to conventional sequencing of FHL2-4, targeted tests for c.118-308C>T and large intronic rearrangement mutations of UNC13D were performed. Haplotype analysis was performed for founder effects using polymorphic markers in the FHL3 locus. FHL mutations were detected in 20 patients (28?%). Seventeen patients had UNC13D mutations (FHL3, 85?%) and three had PRF1 mutations (FHL2, 15?%). UNC13D:c.118-308C>T was detected in ten patients, accounting for 38?% of all mutant alleles of UNC13D, followed by c.754-1G>C (26?%). Haplotype analyses revealed significantly shared haplotypes in both c.118-308C>T and c.754-1G>C, indicating the presence of founder effects. The deep intronic mutation UNC13D:c.118-308C>T accounts for the majority of previously missing mutations and is the most frequent mutation in FHL3 in Korea. Founder effects of two recurrent intronic mutations of UNC13D explain the unusual predominance of FHL3 in Korea.

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