Abstract：Objective To investigate frequency distribution of gene polymorphisms of PRF1 gene in children with hemophagocytic lymphohistiocytosis (HLH), and to explore whether the possible gene polymorphisms of PRF1 gene confer an increased risk of susceptibility to HLH. Methods Forty-eight children who were diagnosed with HLH between January 2009 and December 2013 (HLH group) and 100 healthy children (control group) were enrolled in this study. The gene polymorphisms in the coding region of PRF1 gene, which consists of three exons and two introns, were genotyped by PCR, followed by direct sequencing. Results Three single nucleotide polymorphisms (SNPs) were revealed in the coding sequence of PRF1 in the 48 children with HLH. Seven SNPs were detected in the noncoding sequence. Other two SNPs in the noncoding sequence including rs10999426 and rs10999427 were detected only in 5 healthy children (5%). There was no significant difference in allelic frequencies of all the SNPs above between the HLH and control groups (P>0.05). Haplotype analysis showed there was a pair-wise linkage disequilibrium between rs10999426 and rs10999427 (D=1, r2=1), but there was no significant difference in the distribution of A-T haplotype between the HLH and control groups (P>0.05). Conclusions There is no association between gene polymorphisms of PRF1 gene and the susceptibility to HLH. There is a pair-wise linkage disequilibrium between rs10999426 and rs10999427, but a low detection rate of A-T haplotype in healthy children indicates that it might not play a protective role in the development of HLH.
HUANG Xiao-Hua,LUO Jian-Ming,BIN Qiong et al. Association between gene polymorphisms of Perforin 1 and hemophagocytic lymphohistiocytosis[J]. CJCP, 2015, 17(7): 677-682.
Risma K, Jordan MB. Hemophagocytic lymphohistiocytosis: updates and evolving concepts[J]. Curr Opin Pediatr, 2012, 24(1): 9-15.
[2]
Janka GE. Fami l ial and acquired hemophagocytic lymphohistiocytosis[J]. Annu Rev Med, 2012, 63: 233-246.
[3]
Gholam C, Grigoriadou S, Gilmour KC, et al. Familial haemophagocytic lymphohistiocytosis: advances in the genetic basis, diagnosis and management[J]. Clin Exp Immunol, 2011, 163(3): 271-283.
[4]
Ta n g YM, Xu XJ. Advances in hemophagocytic lymphohistiocytosis: pathogenesis, early diagnosis/differential diagnosis, and treatment[J]. Scientific World Journal, 2011, 11(1): 697-708.
[5]
Voskoboinik I, Thia MC, Trapani JA. A functional analysis of the putative polymorphisms A91V and N252S and 22 missense perforin mutations associated with familial hemophagocytic lymphohistiocytosis[J]. Blood, 2005, 105(12): 4700-4706.
[6]
Sanchez IP, Leal-Esteban LC, Alvarez-Alvarez JA, et al. Analyses of the PRF1 gene in individuals with hemophagocytic lymphohystiocytosis reveal the common haplotype R54C/A91V in Colombian unrelated families associated with late onset disease[J]. J Clin Immunol, 2012, 32(4): 670-680.
[7]
Martinez-Pomar N, Lanio N, Romo N, et al. Functional impact of A91V mutation of the PRF1 perforin gene[J]. Hum Immunol, 2013, 74(1): 14-17.
[8]
Trambas C, Gallo F, Pende D, et al. A single amino acid change, A91V, leads to conformational changes that can impair processing to the active form of perforin[J]. Blood, 2005, 106(3): 932-937.
[9]
H e n t e r J I, H o r n e A, Arico M, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis[J]. Pediatr Blood Cancer, 2007, 48(2): 124-131.
[10]
Zur Stadt U, Beutel K, Kolberg S, et al. Mutation spectrum in children with primary hemophagocytic lymphohistiocytosis: molecular and functional analyses of PRF1, UNC13D, STX11, and RAB27A[J]. Hum Mutat, 2006, 27(1): 62-68.
[11]
Lichtenheld MG, Olsen KJ, Lu P, et al. Structure and function of human perforin[J]. Nature, 1988, 335(6189): 448-451.
[12]
An O, Gursoy A, Gurgey A, et al. Structural and functional analysis of perforin mutations in association with clinical data of familial hemophagocytic lymphohistiocytosis type 2 (FHL2) patients[J]. Protein Sci, 2013, 22(6): 823-839.
[13]
Kägi D, Odermatt B, Seiler P, et al. Reduced incidence and delayed onset of diabetes in perforin-deficient nonobese diabetic mice[J]. J Exp Med, 1997, 186(7): 989-997.
[14]
Cappellano G, Orilieri E, Comi C, et al. Variations of the perforin gene in patients with multiple sclerosis[J]. Genes Immun, 2008, 9(5): 438-444.
[15]
Manso R, Rodriguez-Pinilla SM, Lombardia L, et al. An A91V SNP in the perforin gene is frequently found in NK/T-Cell lymphomas[J]. PLoS One, 2014, 9(3): e91521.
[16]
Yang L, Liu H, Zhao J, et al. Mutations of perforin gene in Chinese patients with acute lymphoblastic leukemia[J]. Leuk Res, 2011, 35(2): 196-199.
[17]
Trapani JA, Thia KYT, Andrews M, et al. Human perforin mutations and susceptibility to multiple primary cancers[J]. Oncoimmunology, 2013, 2(4): e24185.
[18]
Stepp SE, Dufourcq-Lagelouse R, Le Deist F, et al. Perforin gene defects in familial hemophagocytic lymphohistiocytosis[J]. Science, 1999, 286(2): 1957-1959.
[19]
Arico M, Nespoli L, Maccario R, et al. Natural cytotoxicity impairment in familial haemophagocytic lymphohistiocytosis[J]. Arch Dis Child, 1988, 63(3): 292-296.
[20]
Lee SM, Villanueva J, Sumegi J, et al. Characterisation of diverse PRF1 mutations leading to decreased natural killer cell activity in North American families with haemophagocytic lymphohistiocytosis[J]. J Med Genet, 2004, 41(2): 137-144.
[21]
Ishii E, Ohga S, Imashuku S, et al. Review of hemophagocytic lymphohistiocytosis (HLH) in children with focus on Japanese experiences[J]. Crit Rev Oncol Hematol, 2005, 53(3): 209-223.
[22]
Nagai K, Yamamoto K, Fujiwara H, et al. Subtypes of familial hemophagocytic lymphohistiocytosis in Japan based on genetic and functional analyses of cytotoxic T lymphocytes[J]. PLoS One, 2010, 5(11): e14173.
[23]
Okur H, Balta G, Akarsu N, et al. Clinical and molecular aspects of Turkish familial hemophagocytic lymphohistiocytosis patients with perforin mutations[J]. Leuk Res, 2008, 32(6): 972-975.
[24]
Lu G, Xie Z, Shen K, et al. Mutations in the perforin gene in children with hemophagocytic lymphohistiocytosis[J]. Chin Med J (Engl), 2009, 31(23): 2851.
