中文概要
目 的
探究 MARVELD2 在中国非综合征耳聋 (NSHL) 人群中的突变频谱和突变频率。
创新点
发现 MARVELD2 突变频谱具有明显种族特异性。 中国 NSHL 人群中的突变位点及频率不同于已报道的其他人群, 并首次筛选到新致聋候选突变 MARVELD2 c.730G>A。 本研究有助于进一步阐释 MARVELD2 在 NSHL 中的作用。
方 法
收集 283 例 NSHL 患者外周血, 提取基因组 DNA, 涉及 9 对引物覆盖 MARVELD2 基因编码区, 经聚合酶链反应 (PCR) 扩增后 Sanger 测序。 测序结果与参考序列比对, 获得的 MARVELD2 变异位点通过正常人群频率比较、 氨基酸保守性分析、 氨基酸性质分析、 SIFT 和 PolyPhen 有害性预测及蛋白结构功能预测分析等进一步筛选得到耳聋候选突变位点。
结论
中国 NSHL 人群的 MARVELD2 突变位点与巴基斯坦人群, 以及斯洛伐克、 匈牙利和捷克罗马人群不同, 具有明显的种族特异性。 本研究在 283 个 NSHL 病例中共鉴定了 11 个变异位点。 其中, c.730G>A 突变可能影响 MARVELD2 蛋白的正常功能, 与 NSHL 致病有较高的相关性, 是一个候选致聋突变。
References
Adzhubei I, Jordan DM, Sunyaev SR, 2013. Predicting functional effect of human missense mutations using polyphen–2. Curr Protoc Hum Genet, 76(1):7.20.1–7.20.41. https://doi.org/10.1002/0471142905.hg0720s76
Babanejad M, Fattahi Z, Bazazzadegan N, et al., 2012. A comprehensive study to determine heterogeneity of autosomal recessive nonsyndromic hearing loss in Iran. Am J Med Genet A, 158A(10):2485–2492. https://doi.org/10.1002/ajmg.a.35572
Chasman D, Adams RM, 2001. Predicting the functional consequences of non–synonymous single nucleotide polymorphisms: structure–based assessment of amino acid variation. J Mol Biol, 307(2):683–706. https://doi.org/10.1006/jmbi.2001.4510
Chishti MS, Bhatti A, Tamim S, et al., 2008. Splice–site mutations in the TRIC gene underlie autosomal recessive nonsyndromic hearing impairment in Pakistani families. J Hum Genet, 53(2):101–105. https://doi.org/10.1007/s10038–007–0209–3
Dror AA, Avraham KB, 2009. Hearing loss: mechanisms revealed by genetics and cell biology. Annu Rev Genet, 43:411–437. https://doi.org/10.1146/annurev–genet–102108–134135
Dror AA, Avraham KB, 2010. Hearing impairment: a panoply of genes and functions. Neuron, 68(2):293–308. https://doi.org/10.1016/j.neuron.2010.10.011
Higashi T, Lenz DR, Furuse M, et al., 2013. A “Tric” to tighten cell–cell junctions in the cochlea for hearing. J Clin Invest, 123(9):3712–3715. https://doi.org/10.1172/JCI69651
Kitajiri SI, Furuse M, Morita K, et al., 2004. Expression patterns of claudins, tight junction adhesion molecules, in the inner ear. Hear Res, 187(1–2): 25–34. https://doi.org/10.1016/s0378–5955(03)00338–1
Krug SM, Amasheh S, Richter JF, et al., 2009. Tricellulin forms a barrier to macromolecules in tricellular tight junctions without affecting ion permeability. Mol Biol Cell, 20(16):3713–3724. https://doi.org/10.1091/mbc.E09–01–0080
Mašindová I, Šoltýsová A, Varga L, et al., 2015. MARVELD2 (DFNB49) mutations in the hearing impaired central European Roma population—prevalence, clinical impact and the common origin. PLoS ONE, 10(4):e0124232. https://doi.org/10.1371/journal.pone.0124232
Morton CC, Nance WE, 2006. Newborn hearing screening—a silent revolution. New Engl J Med, 354(20):2151–2164. https://doi.org/10.1056/NEJMra050700
Nayak G, Varga L, Trincot C, et al., 2015. Molecular genetics of MARVELD2 and clinical phenotype in Pakistani and Slovak families segregating DFNB49 hearing loss. Hum Genet, 134(4):423–437. https://doi.org/10.1007/s00439–015–1532–y
Ng PC, Henikoff S, 2003. SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res, 31(13): 3812–3814. https://doi.org/10.1093/nar/gkg509
Oda Y, Otani T, Ikenouchi J, et al., 2014. Tricellulin regulates junctional tension of epithelial cells at tricellular contacts through Cdc42. J Cell Sci, 127(Pt 19):4201–4212. https://doi.org/10.1242/jcs.150607
Raleigh DR, Marchiando AM, Zhang Y, et al., 2010. Tight junction–associated marvel proteins MarvelD3, tricellulin, and occludin have distinct but overlapping functions. Mol Biol Cell, 21(7):1200–1213. https://doi.org/10.1091/mbc.E09–08–0734
Ramzan K, Shaikh RS, Ahmad J, et al., 2005. A new locus for nonsyndromic deafness DFNB49 maps to chromosome 5q12.3–q14.1. Hum Genet, 116(1–2): 17–22. https://doi.org/10.1007/s00439–004–1205–8
Riazuddin S, Ahmed ZM, Fanning AS, et al., 2006. Tricellulin is a tight–junction protein necessary for hearing. Am J Hum Genet, 79(6):1040–1051. https://doi.org/10.1086/510022
Šafka Brožková D, Laštůvková J, Štěpánková H, et al., 2012. DFNB49 is an important cause of non–syndromic deafness in Czech Roma patients but not in the general Czech population. Clin Genet, 82(6):579–582. https://doi.org/10.1111/j.1399–0004.2011.01817.x
Schraders M, Ruiz–Palmero L, Kalay E, et al., 2012. Mutations of the gene encoding otogelin are a cause of autosomalrecessive nonsyndromic moderate hearing impairment. Am J Hum Genet, 91(5):883–889. https://doi.org/10.1016/j.ajhg.2012.09.012
Smith RJH, Bale JF Jr, White KR, 2005. Sensorineural hearing loss in children. Lancet, 365(9462):879–890. https://doi.org/10.1016/S0140–6736(05)71047–3
Sterkers O, Ferrary E, Amiel C, 1988. Production of inner ear fluids. Physiol Rev, 68(4):1083–1128. https://doi.org/10.1152/physrev.1988.68.4.1083
Teng S, Michonova–Alexova E, Alexov E, 2008. Approaches and resources for prediction of the effects of nonsynonymous single nucleotide polymorphism on protein function and interactions. Curr Pharm Biotechnol, 9(2): 123–133. https://doi.org/10.2174/138920108783955164
Wang Y, Virtanen J, Xue ZD, et al., 2017. I–TASSER–MR: automated molecular replacement for distant–homology proteins using iterative fragment assembly and progressive sequence truncation. Nucleic Acids Res, 45(W1): W429–W434. https://doi.org/10.1093/nar/gkx349
Yang JY, Zhang Y, 2015. I–TASSER server: new development for protein structure and function predictions. Nucleic Acids Res, 43(W1): W174–W181. https://doi.org/10.1093/nar/gkv342
Yang JY, Yan RX, Roy A, et al., 2015. The I–TASSER suite: protein structure and function prediction. Nat Methods, 12(1):7–8. https://doi.org/10.1038/nmeth.3213
Zheng J, Ying ZB, Cai ZY, et al., 2015. GJB2 mutation spectrum and genotype–phenotype correlation in 1067 Han Chinese subjects with non–syndromic hearing loss. PLoS ONE, 10(6):e0128691. https://doi.org/10.1371/journal.pone.0128691
Acknowledgements
We thank the patients and their families for the participation in this study.
Author information
Authors and Affiliations
Corresponding author
Additional information
Project supported by the National Basic Research Priorities Program of China (Nos. 2014CB541702 and 2014CB541704), the National Natural Science Foundation of China (Nos. 81470685 and 81600817), and the Zhejiang Provincial Public Welfare Technology Applied Research Project (No. 2016C33148), China
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Zheng, J., Meng, Wf., Zhang, Cf. et al. New SNP variants of MARVELD2 (DFNB49) associated with non-syndromic hearing loss in Chinese population. J. Zhejiang Univ. Sci. B 20, 164–169 (2019). https://doi.org/10.1631/jzus.B1700185
Published:
Issue Date:
DOI: https://doi.org/10.1631/jzus.B1700185