318例非综合征型聋人群GJB6基因突变分析（1例同时携带GJB2和GJB6基因缺失突变的耳聋家系）

郑斌娇; 张婷; 王辉; 唐霄雯; 郑静; 吕建新; 管敏鑫

doi:10.13201/j.issn.1001-1781.2016.12.003

318例非综合征型聋人群GJB6基因突变分析（1例同时携带GJB2和GJB6基因缺失突变的耳聋家系）

- 1 温州医科大学Attardi线粒体生物医学研究院(浙江温州, 325035);
- 2 温岭市第一人民医院检验科;
- 3 浙江大学遗传学研究所;
- 4 浙江省医学遗传学重点实验室
基金项目:
国家重点基础研究发展计划(973计划)(No:2014CB541700)

国家青年科学基金(No:31100903)

浙江省自然科学基金(No:Y2110399,Y12H130001)

温州医科大学学生科研项目重点资助(No:wyx2015101001)

详细信息

通讯作者: 管敏鑫,E-mail:gminxin88@zju.edu.cn

中图分类号: R764.43

收稿日期: 2016-02-19

Spectrum of GJB6 variants in 318 pedigrees with non-syndromic hearing loss:one deafness pedigree carrying both GJB6 and GJB2 deletion variant

- 1 Attardi Institute of Mitochondrial Biomedicine and Zhejiang Provincial Key Laboratory of Medical Genetics, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China;
- 2 Department of Clinical Medicine Center, the First People's Hospital of Wenling;
- 3 Department of Genetics, College of Life Sciences, Zhejiang University;
- 4 Zhejiang Provincial Key Laboratory of Medical Genetics

More Information

Corresponding author: GUAN Minxin, E-mail: gminxin88@zju.edu.cn

Received Date: 19 February 2016

摘要

摘要: 目的: 了解318例非综合征型聋人群缝隙连接蛋白B6(GJB6)基因突变的携带情况。方法: 利用PCR方法扩增318例非综合征型聋人群GJB6 基因编码区,用基因芯片与二代测序法对可能携带致病GJB6 突变家系全体成员进行118个已知的耳聋基因检测。结果: 绘制了318例中国汉族非综合征型聋人群的GJB6 基因突变频谱,发现1例同时携带GJB6 和 GJB2 基因缺失突变的中国汉族非综合征型聋家系,经临床和分子遗传学分析发现,该家系成员在发病年龄、听力曲线和听力损失程度上存在差异。突变分析显示,该家系成员同时携带了 GJB2 基因235 delC^+/-突变和GJB6 基因228 delG^+/-突变。其中,GJB6 基因228 del G缺失突变是未报道过的新的位点变异。该缺失位于GJB6 基因高度保守的编码区,在19个物种中的保守性指数达100%。结论: GJB6 基因228 del G缺失突变导致框架移码,转录时在第81位提前出现终止密码子,翻译的多肽比野生型蛋白少了181个氨基酸,可能是新的非综合征型聋相关的致病突变,但仍需进一步的功能研究验证。
- GJB6基因 /
- 缺失突变 /
- 缝隙连接 /
- 聋
Abstract: Objective: To investigate the mutation characteristics of GJB6 (gap juction bata 6) gene in 318 Han Chinese pedigrees with non-syndromic hearing loss.Method: Polymerase chain reaction was used to detect the coding region of GJB6 gene in 318 Han Chinese pedigrees with non-syndromic hearing loss. Gene arrays and second generation sequencing were used to detect 118 genes which had reported to be accosiated with deafness in members of pedigree which possibly carried pathogenic GJB6 gene mutation.Result: Here, we have screened the mutations of GJB6 gene in 318 Han Chinese pedigrees with non-syndromic hearing loss and found one pedigree carrying both GJB6 and GJB2 gene deletion. Clinical and molecular genetic evaluation revealed the variable phenotype of hearing impairments including age-at-onset, audiometric configuration and severity in these subjects. Mutational analysis of the GJB2 and GJB6 gene coding region showed a heterozygous 235 del C of GJB2 gene and a novel 228 del G of GJB6 gene.Conclusion: GJB6 gene 228 del G variant, which occurs at a highly evolutionarily conserved nucleotide, forward the stop codon to 81 position and result in the corresponding polypeptide 181 amino acids shorter than wildtype polypeptide. In addition, GJB6 gene 228 del G absent varies among 94 unrelated Chinese controls. Our finding suggest that GJB6 gene 228 del G maybe a novel pathogenic mutation associated with non-syndromic hearing loss.
- gap junction bata 6 /
- deletionmutation /
- gap junction /
- deafness

HTML全文

参考文献(22)

[1]	姬灿灿,王震英,燕鹏荣,等.GJB6基因突变体过表达慢病毒载体的构建及其在HaCaT细胞中的表达[J].中国麻风皮肤病杂志,2015,31(1):11-14.
[2]	GRILLO A P,DE OLIVERIA F M,DE CARVALHO G Q,et al.Single nucleotide polymorphisms of the GJB2 and GJB6 genes are associated with autosomal recessive nonsyndromic hearing loss[J].Biomed Res Int,2015,2015:318727.
[3]	TEUBNE B,MICHEL V,PESCH J,et al.Connexin30(GJB6)-deficiency causes severe hearing impairment and lack of endocochlear potential[J].Hum Mol Genet,2003,12:13-21.
[4]	LIU Y T,GUO K,LI J,et al.Novel mutations in GJB6 and GJB2 in Clouston syndrome[J].Clin Exp Dermatol,2015,40:770-773.
[5]	CASTRO L S,MARINHO A N,RODRIGUES E M,et al.A study of GJB2 and del GJB6-D13S1830 mutations in Brazilian non-syndromic deaf children from the Amazon region[J].Braz J Otorhinolaryngol,2013,79:95-99.
[6]	DZHEMILEVA L U,BARASHKOV N A,POSUKH O L,et al.Carrier frequency of GJB2 gene mutations c.35delG,c.235delC and c.167delT among the populations of Eurasia[J].J Hum Genet,2010,55:749-754.
[7]	余啸,陈波蓓,项海杰,等.221例携带GJB2基因突变的非综合征型耳聋先证者及家系成员基因型与听力损失程度的相关分析[J].中华耳鼻咽喉头颈外科杂志,2013,48(12):991-995.
[8]	WU B L,LINDEMAN N,LIP V,et al.Effectiveness of sequencing connexin 26(GJB2)in cases of familial or sporadic childhood deafness referred for molecular diagnostic testing[J].Genet Med,2002,4:279-288.
[9]	GRIFA A,WAGNER C A,D'AMBROSIO L,et al.Mutations in GJB6 cause nonsyndromic autosomal dominant deafness at DFNA 3locus[J].Nat Genet,1999,23:16-18.
[10]	MAHDIEH N,RABBANI B,WILEY S,et al.Genetic causes of nonsyndromic hearing loss in Iran in comparison with other populations[J].J Hum Genet,2010,55:639-648.
[11]	DEL CASTILLO I,VILLAMAR M,MMRENOPELAYO M A,et al.A deletion involving the connexin 30 gene in nonsyndromic hearing impairment[J].N Engl J Med,2002,346:243-249.
[12]	BHALLA S,SHARMA R,KHANDELWAL G,et al.Absence of GJB6 mutations in Indian patients with non-syndromic hearing loss[J].Int J Pediatr Otorhinolaryngol,2011,75:356-359.
[13]	HERNANDEZ-JUAREZ A A,LUGO-TRAMPE JDE J,CAMPOS-ACEVEDO L D,et al.GJB2 and GJB6 mutations are an infrequent cause of autosomal-recessive nonsyndromic hearing loss in residents of Mexico[J].Int J Pediatr Otorhinolaryngol,2014,78:2107-2112.
[14]	YUAN Y,ZHANG X,HUANG S,et al.Common molecular etiologies are rare in nonsyndromic Tibetan Chinese patients with hearing impairment[J].PLoS One,2012,7:e30720.
[15]	万亚蕊,张延平,孙建和,等.GJB6基因敲除小鼠耳蜗血管纹超微结构观察[J].中国听力语言康复科学杂志,2014,12(1):44-47.
[16]	KELLY J J,SHAO Q,JAGGER D J,et al.Cx30exhibits unique characteristics including a long halflife when assembled into gap junctions[J].J Cell Sci,2015,128:3947-3960.
[17]	KIKUCHI T,KIMURA R S,PAUL D L,et al.Gap junction systems in the mammalian cochlea[J].Brain Res Brain Res Rev,2000,32:163-166.
[18]	FORGE A,JAGGER D J,KELLY J J,et al.Connexin30-mediated intercellular communication plays an essential role in epithelial repair in the cochlea[J].J Cell Sci,2013,126:1703-1712.
[19]	袁永一,黄德亮,戴朴,等.中国非综合征遗传性聋人群GJB6基因突变分析[J].临床耳鼻咽喉头颈外科杂志,2007,21(1):3-6.
[20]	陈垲钿,宗凌,周蔚,等.200例非综合征型聋患者GJB3和GJB6基因突变分析[J].听力学及言语疾病杂志,2012,20(3):198-200.
[21]	PANDYA A,ARNOS K S,XIA X J,et al.Frequency and distribution of GJB2(connexin 26)and GJB6(connexin 30)mutations in a large North Amerivan repository of deaf probands[J].Genet Med,2003,5:295-303.
[22]	ROUX A F,PALLARES-RUIZ N,VIELLE A,et al.Molecular epidemiology of DFNB1 deafness in France[J].BMC Med Genet,2004,5:5-14.