常染色体隐性遗传先天性角化不良一例及TERT基因突变研究

doi:10.35541/cjd.20200057

中华皮肤科杂志 ›› 2020, Vol. 53 ›› Issue (11): 875-879.doi: 10.35541/cjd.20200057

常染色体隐性遗传先天性角化不良一例及TERT基因突变研究

黄茂欣¹ 于建斌¹ 刘莉娜² 李小红¹ 张江安¹

¹郑州大学第一附属医院皮肤科 450052；²郑州大学第一附属医院遗传与产前诊断中心 450052

收稿日期:2020-02-02 修回日期:2020-09-03 发布日期:2020-11-03
通讯作者: 于建斌；刘莉娜 E-mail:Yu Jianbin; liulina5965@163.com
基金资助:
郑州大学遗传性皮肤病研究生联合培养基地建设项目（YJSCXJD201908）

Autosomal recessive dyskeratosis congenita: a case report and TERT gene mutation analysis

Huang Maoxin¹, Yu Jianbin¹, Liu Lina², Li Xiaohong¹, Zhang Jiang′an¹

¹Department of Dermatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; ²Center of Hereditary and Prenatal Diagnosis, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China

Received:2020-02-02 Revised:2020-09-03 Published:2020-11-03
Contact: Yu Jianbin; Liu Lina E-mail:Yu Jianbin; liulina5965@163.com
Supported by:
Construction Project of Joint Training Base for Postgraduates in Genetic Skin Diseases of Zhengzhou University （YJSCXJD201908）

摘要/Abstract

摘要： 【摘要】目的报告1例常染色体隐性遗传先天性角化不良，检测其致病基因突变情况。方法采集先证者及其父母外周血，提取基因组DNA，以100例健康人作为对照，运用Illumina Nextseq500测序仪检测先证者家系皮肤病相关基因编码区域的序列突变情况，致病性突变经PCR?Sanger测序验证。运用生物信息学软件Clustalw2.0、PyMOL、PolyPhen?2、SIFT及FATHMM分别对基因突变位点的保守性、蛋白结构变化及致病性进行预测。结果先证者临床表现为颈胸部网状皮肤异色、腋窝点状色素沉着，部分趾甲萎缩、表面粗糙及口腔黏膜白斑，血常规及肝功能指标部分异常。基因检测显示，先证者携带TERT基因c.2452G>A（p.Val818Met）与c.2594G>A（p.Arg865His）复合杂合突变，其中c.2452G>A突变在HGMD中未见收录。母亲携带c.2452G>A杂合突变，父亲及100例健康对照TERT基因未见突变。生物信息软件分析显示，多个物种TERT蛋白在818与865位氨基酸位点分别为高度保守与完全保守，基因突变后对应蛋白结构存在差异。依先证者临床表现、基因检测、辅助检查及生物信息分析结果，最终诊断为常染色体隐性遗传先天性角化不良。结论 TERT基因c.2594G>A（p.Arg865His）与c.2452G>A（p.Val818Met）复合杂合突变可能是导致该先证者临床表型的原因。

关键词: 先天性角化不良, DNA突变分析, 皮肤表现, 基因, TERT

Abstract: 【Abstract】 Objective To report a case of autosomal recessive dyskeratosis congenita, and to detect mutations in its causative genes. Methods Peripheral blood samples were collected from the proband and her parents, genomic DNA was extracted, and 100 unrelated healthy individuals served as controls. The Illumina Nextseq500 sequencer was used to detect sequence variations in coding regions of exons of the skin disease-related genes in the proband′s family, and the causative mutation was verified by PCR-Sanger sequencing. The conservation and pathogenicity of gene mutation sites and corresponding protein structure changes were predicted by using bioinformatics softwares Clustalw2.0, PyMOL, PolyPhen-2, SIFT and FATHMM. Results The proband clinically presented with reticular poikilodermatous patches on the neck and chest, punctate pigmentation on the axilla, atrophy of some toenails, rough skin and oral leukoplakia, accompanied by abnormality in some indicators of routine blood tests and liver function. Genetic testing showed that the proband carried compound heterozygous mutations c.2452G>A （p.Val818Met） and c.2594G>A （p.Arg865His） in the TERT gene, and the c.2452G>A mutation was not included in the Human Gene Mutation Database. The proband′s mother carried a heterozygous mutation c.2452G>A, and no mutation was identified in the TERT gene of her father or 100 healthy controls. Bioinformatics analysis showed that the amino acid positions 818 and 865 of TERT proteins in multiple species were highly conserved and completely conserved respectively, and the corresponding protein structures changed after the above gene mutations. Based on the clinical manifestations, genetic testing, auxiliary examinations, and bioinformatics analysis results, the patient was finally diagnosed with autosomal recessive dyskeratosis congenita. Conclusion The compound heterozygous mutations c.2594G>A （p.Arg865His） and c.2452G>A （p.Val818Met） in the TERT gene may be responsible for the clinical phenotype of the proband.

Key words: Dyskeratosis congenita, DNA mutational analysis, Skin manifestations, Gene, TERT

黄茂欣于建斌刘莉娜李小红张江安. 常染色体隐性遗传先天性角化不良一例及TERT基因突变研究[J]. 中华皮肤科杂志, 2020,53(11):875-879. doi:10.35541/cjd.20200057

Huang Maoxin, Yu Jianbin, Liu Lina, Li Xiaohong, Zhang Jiang′an. Autosomal recessive dyskeratosis congenita: a case report and TERT gene mutation analysis[J]. Chinese Journal of Dermatology, 2020, 53(11): 875-879.doi:10.35541/cjd.20200057

参考文献 24

［1］	Sorrow JM Jr, Hitch JM. Dyskeratosis congenita. First report of its occurrence in a female and a review of the literature［J］. Arch Dermatol, 1963,88:340⁃347. doi: 10.1001/archderm.1963.01590 210098015.
［2］	Sirinavin C, Trowbridge AA. Dyskeratosis congenita: clinical features and genetic aspects. Report of a family and review of the literature［J］. J Med Genet, 1975,12（4）:339⁃354. doi: 10. 1136/jmg.12.4.339.
［3］	Ballew BJ, Savage SA. Updates on the biology and management of dyskeratosis congenita and related telomere biology disorders［J］. Expert Rev Hematol, 2013,6（3）:327⁃337. doi: 10.1586/ehm. 13.23.
［4］	Glousker G, Touzot F, Revy P, et al. Unraveling the pathogenesis of Hoyeraal⁃Hreidarsson syndrome, a complex telomere biology disorder［J］. Br J Haematol, 2015,170（4）:457⁃471. doi: 10.1111/bjh.13442.
［5］	Elliott AM, Graham GE, Bernstein M, et al. Dyskeratosis congenita: an autosomal recessive variant［J］. Am J Med Genet, 1999,83（3）:178⁃182. doi: 10.1002/（sici）1096⁃8628（19990319） 83:33.0.co;2⁃3.
［6］	Drachtman RA, Alter BP. Dyskeratosis congenita［J］. Dermatol Clin, 1995,13（1）:33⁃39.
［7］	Walne AJ, Vulliamy T, Beswick R, et al. Mutations in C16orf57 and normal⁃length telomeres unify a subset of patients with dyskeratosis congenita, poikiloderma with neutropenia and Rothmund⁃Thomson syndrome［J］. Hum Mol Genet, 2010,19（22）:4453⁃4461. doi: 10.1093/hmg/ddq371.
［8］	Diaz de Leon A, Cronkhite JT, Katzenstein AL, et al. Telomere lengths, pulmonary fibrosis and telomerase （TERT） mutations［J/OL］. PLoS One, 2010,5（5）:e10680. doi: 10.1371/journal.pone. 0010680.
［9］	Pestana A, Vinagre J, Sobrinho⁃Simões M, et al. TERT biology and function in cancer: beyond immortalisation［J］. J Mol Endocrinol, 2017,58（2）:R129⁃R146. doi: 10.1530/JME⁃16⁃0195.
［10］	Imamura S, Uchiyama J, Koshimizu E, et al. A non⁃canonical function of zebrafish telomerase reverse transcriptase is required for developmental hematopoiesis［J/OL］. PLoS One, 2008,3（10）:e3364. doi: 10.1371/journal.pone.0003364.
［11］	Tsakiri KD, Cronkhite JT, Kuan PJ, et al. Adult⁃onset pulmonary fibrosis caused by mutations in telomerase［J］. Proc Natl Acad Sci U S A, 2007,104（18）:7552⁃7557. doi: 10.1073/pnas.0701 009104.
［12］	Du HY, Pumbo E, Manley P, et al. Complex inheritance pattern of dyskeratosis congenita in two families with 2 different mutations in the telomerase reverse transcriptase gene［J］. Blood, 2008,111（3）:1128⁃1130. doi: 10.1182/blood⁃2007⁃10⁃120907.
［13］	Walne AJ, Vulliamy T, Kirwan M, et al. Constitutional mutations in RTEL1 cause severe dyskeratosis congenita［J］. Am J Hum Genet, 2013,92（3）:448⁃453. doi: 10.1016/j.ajhg.2013.02.001.
［14］	Batista LF, Pech MF, Zhong FL, et al. Telomere shortening and loss of self⁃renewal in dyskeratosis congenita induced pluripotent stem cells［J］. Nature, 2011,474（7351）:399⁃402. doi: 10.1038/nature10084.
［15］	Yamaguchi H, Calado RT, Ly H, et al. Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia［J］. N Engl J Med, 2005,352（14）:1413⁃1424. doi: 10.1056/NEJMoa 042980.
［16］	Ballew BJ, Savage SA. Updates on the biology and management of dyskeratosis congenita and related telomere biology disorders［J］. Expert Rev Hematol, 2013,6（3）:327⁃337. doi: 10.1586/ehm. 13.23.
［17］	Walne AJ, Vulliamy T, Beswick R, et al. Mutations in C16orf57 and normal⁃length telomeres unify a subset of patients with dyskeratosis congenita, poikiloderma with neutropenia and Rothmund⁃Thomson syndrome［J］. Hum Mol Genet, 2010,19（22）:4453⁃4461. doi: 10.1093/hmg/ddq371.
［18］	Youssefian L, Vahidnezhad H, Barzegar M, et al. The Kindler syndrome: a spectrum of FERMT1 mutations in Iranian families［J］. J Invest Dermatol, 2015,135（5）:1447⁃1450. doi: 10.1038/jid.2015.9.
［19］	German J, Sanz MM, Ciocci S, et al. Syndrome⁃causing mutations of the BLM gene in persons in the Bloom′s Syndrome Registry［J］. Hum Mutat, 2007,28（8）:743⁃753. doi: 10.1002/humu.20501.
［20］	Zhang Z, Zhang J, Chen F, et al. Family of hereditary fibrosing poikiloderma with tendon contractures, myopathy and pulmonary fibrosis caused by a novel FAM111B mutation［J］. J Dermatol, 2019,46（11）:1014⁃1018. doi: 10.1111/1346⁃8138.15045.
［21］	Saijo M, Takedachi A, Tanaka K. Nucleotide excision repair by mutant xeroderma pigmentosum group A （XPA） proteins with deficiency in interaction with RPA［J］. J Biol Chem, 2011,286（7）:5476⁃5483. doi: 10.1074/jbc.M110.172916.
［22］	Ogden GR, Connor E, Chisholm DM. Dyskeratosis congenita: report of a case and review of the literature［J］. Oral Surg Oral Med Oral Pathol, 1988,65（5）:586⁃591. doi: 10.1016/0030⁃4220（88）90142⁃9.
［23］	Nelson AS, Marsh RA, Myers KC, et al. A reduced⁃intensity conditioning regimen for patients with dyskeratosis congenita undergoing hematopoietic stem cell transplantation［J］. Biol Blood Marrow Transplant, 2016,22（5）:884⁃888. doi: 10.1016/j.bbmt.2016.01.026.
［24］	Li F, Li W, Qiao X, et al. Clinical features of dyskeratosis congenita in mainland China: case reports and literature review［J］. Int J Hematol, 2019,109（3）:328⁃335. doi: 10.1007/s12185⁃018⁃02582⁃x.

[1]	王雯竹王宝玺何艳艳徐浩翔. 化脓性汗腺炎/反常性痤疮的分型进展[J]. 中华皮肤科杂志, 2023, 56(9): 892-895.
[2]	陈春里闫思聿王丹高丽华谭丽娜唐四元刘伟曾金容鲁建云. 酸化脂肪酸酯治疗特应性皮炎样模型小鼠的疗效及机制初探[J]. 中华皮肤科杂志, 2023, 56(9): 822-831.
[3]	张俐施健葛鑫刘念念陈赛张冬梅缪旭. Brahma相关基因1与激活转录因子2相互作用对皮肤鳞状细胞癌细胞增殖、迁移和侵袭能力的影响[J]. 中华皮肤科杂志, 2023, 56(8): 724-736.
[4]	王莉任增果娄桂予张玉薇杨科雷星星张冰廖世秀郝冰涛. 两个营养不良型大疱性表皮松解症家系的基因诊断[J]. 中华皮肤科杂志, 2023, 56(8): 770-773.
[5]	贾韬宋相瑾耿松梅. 自身炎症性皮肤病[J]. 中华皮肤科杂志, 2023, 56(8): 794-799.
[6]	李越吴金燕袁若月杨屈杨赵贤省朱宁文. 细胞治疗遗传性大疱性表皮松解症研究进展[J]. 中华皮肤科杂志, 2023, 56(7): 698-702.
[7]	宋德宇王嘉玥耿佳邹美熔李仲桃陈玉沙汪盛. GJB2基因p.N54H突变致经典型Vohwinkel综合征1例[J]. 中华皮肤科杂志, 2023, 56(7): 669-672.
[8]	李翔倩赵永平赵梦曦周城. LSS基因突变导致先天性少毛症14型1家系[J]. 中华皮肤科杂志, 2023, 56(7): 672-676.
[9]	黄晓燕肖易敬丹榕陈明亮沈敏学. 湖南省某砷尾矿地区居民砷中毒皮肤损害患病率及相关因素调查[J]. 中华皮肤科杂志, 2023, 56(7): 636-641.
[10]	孙蔺波徐教生. Curry-Jones综合征1例国内首报[J]. 中华皮肤科杂志, 2023, 56(7): 626-629.
[11]	魏瑾闫会文赵天威冉立伟伦文辉张建中. 乳头乳晕湿疹样透明细胞棘皮瘤：国内首报及文献分析[J]. 中华皮肤科杂志, 2023, 56(6): 545-548.
[12]	孙玉姣王建波段紫钰窦进法李彦李建国张守民. 泛发性家族性良性慢性天疱疮1家系ATP2C1基因变异检测[J]. 中华皮肤科杂志, 2023, 56(4): 335-337.
[13]	任发亮王华肖异珠. 透明细胞丘疹病57例临床特征分析[J]. 中华皮肤科杂志, 2023, 56(4): 309-312.
[14]	杨剑秋刘倩楠周生儒李敏. 化脓性关节炎、坏疽性脓皮病、痤疮综合征1例并文献回顾[J]. 中华皮肤科杂志, 2023, 0(3): 20230253-e0230253.
[15]	张帅邵依张守民李振鲁李建国王建波. 结节性硬化症并发反常性痤疮1例的临床表现及基因变异分析[J]. 中华皮肤科杂志, 2023, 0(3): 20230268-e20230268.

常染色体隐性遗传先天性角化不良一例及TERT基因突变研究

Autosomal recessive dyskeratosis congenita: a case report and TERT gene mutation analysis

PDF

可视化

摘要/Abstract

引用本文

使用本文

参考文献 24

相关文章 15

Metrics

本文评价

推荐阅读 10