PIK3CD基因突变致PI3K-δ过度活化综合征1例报告并文献复习
|
摘要
目的了解PI3K-δ过度活化综合征的临床特征及致病基因。方法回顾分析1例PI3K-δ过度活化综合征患儿的临床资料。结果患儿,男,3岁10个月,反复呼吸道感染,肝脾肿大,发育落后。提取患儿及父母外周血DNA,通过全外显子组测序及Sanger验证,证实患儿PIK3CD基因存在错义变异c.3061G>A(E1021K),先证者父母PIK3CD基因均未发现上述变异,为新生变异。该突变使PIK3CD基因发生功能获得性突变,导致编码的p110δ活性增强,PI3K-PIP3-AKT-mTOR信号通路过度激活,诱导细胞分化增殖,致疾病发生,为致病性突变。结论 PI 3 K-δ过度活化综合征为罕见的常染色体显性遗传免疫缺陷病,基因检测可协助诊断。
Objective To explore the clinical characteristics and pathogenic genes of activated PI3 K-δ syndrome(APDS). Method The clinical data of APDS in a child was retrospectively analyzed. Results A boy aged 3 years and 9 months presented recurrent respiratory infections, hepatosplenomegaly and growth retardation. The DNA was extracted from the peripheral blood of the child and his parents. The sequence analyses were performed by whole exome sequencing technology and the mutant gene was validated by Sanger sequencing. A novel heterozygous missense mutation(De novo), c.3061 G>A(E1021 K),was found in the PIK3 CD gene in the child, and both his parents had normal genotypes. PIK3 CD gain-of-function mutations leads to enhanced activity of the encoded p110δ. The PI3 K-PIP3-AKT-mTOR signaling pathway is over-activated, which induces cell differentiation and proliferation, and thus the disease is caused. So the mutation is a pathogenic mutation. Conclusion PI3 K-δoveractivation syndrome is a rare autosomal dominant immunodeficiency disease, and genetic testing can assist the diagnosis.
Objective To explore the clinical characteristics and pathogenic genes of activated PI3 K-δ syndrome(APDS). Method The clinical data of APDS in a child was retrospectively analyzed. Results A boy aged 3 years and 9 months presented recurrent respiratory infections, hepatosplenomegaly and growth retardation. The DNA was extracted from the peripheral blood of the child and his parents. The sequence analyses were performed by whole exome sequencing technology and the mutant gene was validated by Sanger sequencing. A novel heterozygous missense mutation(De novo), c.3061 G>A(E1021 K),was found in the PIK3 CD gene in the child, and both his parents had normal genotypes. PIK3 CD gain-of-function mutations leads to enhanced activity of the encoded p110δ. The PI3 K-PIP3-AKT-mTOR signaling pathway is over-activated, which induces cell differentiation and proliferation, and thus the disease is caused. So the mutation is a pathogenic mutation. Conclusion PI3 K-δoveractivation syndrome is a rare autosomal dominant immunodeficiency disease, and genetic testing can assist the diagnosis.
引文
[1]Angulo I,Vadas O,Garcon F,et al.Phosphoinositide 3-kinase delta gene mutation predisposes to respiratory infection and airway damage[J].Science,2013,342(6160):866-871.
[2]Lucas CL,Kuehn HS,Zhao F,et al.Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110delta result in T cell senescence and human immunodeficiency[J].Nat Immunol,2014,15(1):88-97.
[3]Coulter TI,Chandra A,Bacon CM,et al.Clinical spectrum and features of activated phosphoinositide 3-kinase delta syndrome:a large patient cohort study[J].J Allergy Clin Immunol,2017,139(2):597-606.
[4]Kracker S,Curtis J,Ibrahim MA,et al.Occurrence of B-cell lymphomas in patients with activated phosphoinositide3-kinase delta syndrome[J].J Allergy Clin Immunol,2014,134(1):233-236.
[5]Elgizouli M,Lowe DM,Speckmann C,et al.Activating PI3Kdelta mutations in a cohort of 669 patients with primary immunodeficiency[J].Clin Exp Immunol,2016,183(2):221-229.
[6]唐文静,王薇,罗颖,等.PIK3CD基因突变致PI3Kδ过度活化综合征临床及免疫学特点分析[J].中华儿科杂志,2017,(1):19-24.
[7]Crank MC,Grossman JK,Moir S,et al.Mutations in PIK3CD can cause hyper IgM syndrome(HIGM)associated with increased cancer susceptibility[J].J Clin Immunol,2014,34(3):272-276.
[8]Burke JE,Vadas O,Berndt A,et al.Dynamics of the phosphoinositide 3-kinase p110delta interaction with p85alpha and membranes reveals aspects of regulation distinct from p110alpha[J].Structure,2011,19(8):1127-1137.
[9]Lucas CL,Chandra A,Nejentsev S,et al.PI3Kdelta and primary immunodeficiencies[J].Nat Rev Immunol,2016,16(11):702-714.
[10]Notarangelo LD,Fleisher TA.Targeted strategies directed at the molecular defect:toward precision medicine for select primary immunodeficiency disorders[J].J Allergy Clin Immunol,2017,139(3):715-723.
[11]首都儿科研究所.2015年中国九市七岁以下儿童体格发育调查[J].中华儿科杂志,2018,56(3):192-199.
[12]Davies EG,Thrasher AJ.Update on the hyper immunoglobulin M syndromes[J].Br J Haematol,2010,149(2):167-180.
[2]Lucas CL,Kuehn HS,Zhao F,et al.Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110delta result in T cell senescence and human immunodeficiency[J].Nat Immunol,2014,15(1):88-97.
[3]Coulter TI,Chandra A,Bacon CM,et al.Clinical spectrum and features of activated phosphoinositide 3-kinase delta syndrome:a large patient cohort study[J].J Allergy Clin Immunol,2017,139(2):597-606.
[4]Kracker S,Curtis J,Ibrahim MA,et al.Occurrence of B-cell lymphomas in patients with activated phosphoinositide3-kinase delta syndrome[J].J Allergy Clin Immunol,2014,134(1):233-236.
[5]Elgizouli M,Lowe DM,Speckmann C,et al.Activating PI3Kdelta mutations in a cohort of 669 patients with primary immunodeficiency[J].Clin Exp Immunol,2016,183(2):221-229.
[6]唐文静,王薇,罗颖,等.PIK3CD基因突变致PI3Kδ过度活化综合征临床及免疫学特点分析[J].中华儿科杂志,2017,(1):19-24.
[7]Crank MC,Grossman JK,Moir S,et al.Mutations in PIK3CD can cause hyper IgM syndrome(HIGM)associated with increased cancer susceptibility[J].J Clin Immunol,2014,34(3):272-276.
[8]Burke JE,Vadas O,Berndt A,et al.Dynamics of the phosphoinositide 3-kinase p110delta interaction with p85alpha and membranes reveals aspects of regulation distinct from p110alpha[J].Structure,2011,19(8):1127-1137.
[9]Lucas CL,Chandra A,Nejentsev S,et al.PI3Kdelta and primary immunodeficiencies[J].Nat Rev Immunol,2016,16(11):702-714.
[10]Notarangelo LD,Fleisher TA.Targeted strategies directed at the molecular defect:toward precision medicine for select primary immunodeficiency disorders[J].J Allergy Clin Immunol,2017,139(3):715-723.
[11]首都儿科研究所.2015年中国九市七岁以下儿童体格发育调查[J].中华儿科杂志,2018,56(3):192-199.
[12]Davies EG,Thrasher AJ.Update on the hyper immunoglobulin M syndromes[J].Br J Haematol,2010,149(2):167-180.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |