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目的了解穿孔素基因(PRF1)突变和序列变异在中国儿童噬血细胞综合征(HLH)中的发生情况,探讨基因突变型与临床表现之间可能的关系。方法应用聚合酶链反应(PCR)结合直接测序方法,对2006年1月至2008年5月在首都医科大学附属北京儿童医院治疗的临床诊断为HLH的30例患儿(HLH组)及50名新生儿(对照组)PRF1基因外显子编码区进行突变筛查。结果在3例HLH患儿的PRF1基因外显子编码区发现3个杂合错义突变,这3个突变均导致氨基酸改变(C102F、S108N和T450M),而在对照组中却未发现。1例患儿为复合杂合错义突变(S108N和T450M),从遗传学上可明确诊断为家族性HLH亚型2(FHL2);1个同义序列变异(Q540Q)在1例患儿中发现,而在对照组中未发现;在HLH组和对照组的PRF1基因编码区发现2个单核苷酸多态位点(SNP)(A274A、H300H),但这2个SNP的基因型频率在HLH组和对照组之间的分布差异无统计学意义(P均>0.05)。结论我国HLH患儿中存在PRF1基因突变,而突变位点(C102F和S108N)目前仅在中国患儿中发现。显示了我国HLH患儿PRF1基因突变具有自身的特点。对于无HLH家族史和起病年龄较晚的HLH患儿,也要考虑家族性HLH的可能。
Objective To investigate the occurrence of perforin gene (PRF1) mutation and sequence variation in Chinese children with hemophagocytic syndrome (HLH) and to explore the possible relationship between gene mutation and clinical manifestations. Methods Polymerase chain reaction (PCR) combined with direct sequencing was performed in 30 children with HLH (HLH group) and 50 children (HLH group) clinically diagnosed at Beijing Children’s Hospital Affiliated to Capital Medical University from January 2006 to May 2008. Neonates (control group) PRF1 gene exon coding region mutation screening. Results Three heterozygous missense mutations were found in the exon coding region of PRF1 gene in three children with HLH. All three mutations resulted in amino acid changes (C102F, S108N and T450M) but not in the control group. One patient had a combined heterozygous missense mutation (S108N and T450M) that was genetically diagnostically diagnosed as familial HLH subtype 2 (FHL2), one synonymous sequence variant (Q540Q) in one patient (SNPs) (A274A, H300H) were found in the PRF1 gene coding region of HLH group and control group, but the genotype frequencies of these two SNPs There was no significant difference in the distribution between HLH group and control group (all P> 0.05). Conclusions There are PRF1 gene mutations in children with HLH in China, but the mutation sites (C102F and S108N) are only found in Chinese children. It shows that the mutation of PRF1 in children with HLH has its own characteristics. For HLH children with no family history of HLH and later onset of disease, familial HLH should also be considered.