Detection and Functional Verification of Noncanonical Splice Site Mutations in Hereditary Deafness.
Detection and Functional Verification of Noncanonical Splice Site Mutations in Hereditary Deafness.
复制标题
DOI：
10.3389/fgene.2021.773922
复制
发表时间：
2021
影响因子：
3.7
通讯作者：
Yang T
中科院分区：
文献类型：
--
作者：
Chen P;Wang L;Chai Y;Wu H;Yang T
剪接位点突变是导致包括耳聋在内的孟德尔遗传病的重要原因。通过对4个多基因常染色体显性遗传性耳聋家系和2个单基因常染色体隐性遗传性耳聋家系的新一代测序，我们在已知耳聋基因的非典型剪接位点上发现了多种候选致病性变异，包括EYA 4的c.1616+3A > T和c.580G > A，PAX 3的c.322-57_322-8del，c.991-15_991- 13 del在DFNA 5中，c.6087- 3 T> G在PTPRQ中和c.164+5G > A在USH 1G中。预测所有六种变体通过计算工具人类剪接酶、NNSPLICE和NetGene 2中的至少一种影响RNA剪接。表型分离的变体在所有家庭中得到证实，是与以前报道的相应基因的基因型-表型相关性。小基因分析表明，这些剪接位点变异可能会产生包括外显子跳跃在内的各种负面影响（EYA 4中c.1616+3A > T和c.580G > A，DFNA 5中c.991-15_991- 13 del），内含子保留322 -57_322-8del）、外显子跳跃和内含子保留（PTPRQ中的c.6087- 3 T> G）和外显子缩短（USH 1G中的c.164+5G > A）。我们的研究表明，隐藏的，非典型的剪接位点突变可能在遗传性耳聋的分子病因学中起着重要作用，其诊断可以通过修改下一代测序数据的过滤标准，功能验证，以及分离，生物信息学和基因型-表型相关性分析来促进。
Splice site mutations contribute to a significant portion of the genetic causes for mendelian disorders including deafness. By next-generation sequencing of 4 multiplex, autosomal dominant families and 2 simplex, autosomal recessive families with hereditary deafness, we identified a variety of candidate pathogenic variants in noncanonical splice sites of known deafness genes, which include c.1616+3A > T and c.580G > A in EYA4, c.322-57_322-8del in PAX3, c.991-15_991-13del in DFNA5, c.6087-3T > G in PTPRQ and c.164+5G > A in USH1G. All six variants were predicted to affect the RNA splicing by at least one of the computational tools Human Splicing Finder, NNSPLICE and NetGene2. Phenotypic segregation of the variants was confirmed in all families and is consistent with previously reported genotype-phenotype correlations of the corresponding genes. Minigene analysis showed that those splicing site variants likely have various negative impact including exon-skipping (c.1616+3A > T and c.580G > A in EYA4, c.991-15_991-13del in DFNA5), intron retention (c.322-57_322-8del in PAX3), exon skipping and intron retention (c.6087-3T > G in PTPRQ) and shortening of exon (c.164+5G > A in USH1G). Our study showed that the cryptic, noncanonical splice site mutations may play an important role in the molecular etiology of hereditary deafness, whose diagnosis can be facilitated by modified filtering criteria for the next-generation sequencing data, functional verification, as well as segregation, bioinformatics, and genotype-phenotype correlation analysis.
登录
查看更多内容
中国家庭中由新型复合杂合 PTPRQ 突变引起的常染色体隐性先天性感音神经性听力损失。
影响因子：
3.1
作者：
Wu X;Wang S;Chen S;Wen YY;Liu B;Xie W;Li D;Liu L;Huang X;Sun Y;Kong WJ
通讯作者：
Kong WJ
NLRP3 在螺旋神经节神经元中表达，与综合征性和非综合征性感音神经性耳聋相关
影响因子：
3.1
作者：
Chen P;He L;Pang X;Wang X;Yang T;Wu H
通讯作者：
Wu H
影响因子：
2
作者：
Somashekar, Puneeth H.;Upadhyai, Priyanka;Shukla, Anju
通讯作者：
Shukla, Anju
影响因子：
9.8
作者：
Shearer, A. Eliot;Eppsteiner, Robert W.;Smith, Richard J. H.
通讯作者：
Smith, Richard J. H.
影响因子：
2
作者：
Hildebrand, Michael S.;Coman, David;Dahl, Hans-Henrik M.
通讯作者：
Dahl, Hans-Henrik M.