Q型蛋白酪氨酸磷酸酶受体(Receptor type protein tyrosine phosphatase Q,PTPRQ)是Ⅲ型酪氨酸磷酸酶受体家族的成员,具有磷酸酪氨酸磷酸酶和磷脂酰肌醇磷酸酶活性,可调节细胞的增殖、凋亡、分化等多种细胞内生理过程。在内耳方面,PTPR...Q型蛋白酪氨酸磷酸酶受体(Receptor type protein tyrosine phosphatase Q,PTPRQ)是Ⅲ型酪氨酸磷酸酶受体家族的成员,具有磷酸酪氨酸磷酸酶和磷脂酰肌醇磷酸酶活性,可调节细胞的增殖、凋亡、分化等多种细胞内生理过程。在内耳方面,PTPRQ被认为是一种耳聋基因,主要参与耳蜗和前庭毛细胞的发育及成熟。研究发现,PTPRQ基因突变可导致两种非综合征性遗传性耳聋,包括DFNB84A型常染色体隐性耳聋和DFNA73型常染色体显性耳聋,两种耳聋的临床表型差异很大,这提示了其致病机制的不同。既往研究报道了多个耳聋家系与PTPRQ基因突变相关,本文对此做一综述,有助于识别治疗耳聋相关疾病的新靶点,并为PTPRQ突变致病机理的进一步研究提供理论参考。展开更多
Background： Nonsyndrornic hearing loss （NSHL） is highly heterogeneous, in which more than 90 causative genes have currently been identified. DFNA5 is one of the deathess genes that known to cause autosomal dominant...Background： Nonsyndrornic hearing loss （NSHL） is highly heterogeneous, in which more than 90 causative genes have currently been identified. DFNA5 is one of the deathess genes that known to cause autosomal dominant NSHL. Until date, only five DFN.45 mutations have been described in eight families worldwide. In this study, we reported the identification of a novel pathogenic mutation causing DFNA5 deafness in a five-generation Chinese family. Methods： Alter detailed clinical evaluations of this family, the genomic DNA of three affected individuals was selected for targeted exome sequencing of 101 known deafness genes, as well as mitochondrial DNA and microRNA regions. Co-segregation analysis between the hearing loss and the candidate variant was confirmed in available family members by direct polymerase chain reaction （PCR）-Sanger sequencing. Real-time PCR （RT-PCR） was pertormed to investigate the potential effect of the pathogenic mutation on messenger RNA splicing. Results： Clinical evaluations revealed a similar deafness phenotype in this family to that of previously reported DFNA5 families with autosomal dominant, late-onset bearing loss. Molecular analysis identified a novel splice site mutation in DFNA5 intron 8 （IVSS＋ 1 delG）. The mutation segregated with the hearing loss of the family and was absent in 120 unrelated control DNA samples of Chinese origin. RT-PCR showed skipping of exon 8 in the mutant transcript. Conclusions： We identified a novel DFNA5 mutation IVS8＋1 delG in a Chinese family which led to skipping ofexon 8. This is the sixth DFNA5 mutation relates to hearing loss and the second one in DFNA5 intron 8. Our findings provide further support to the hypothesis that the DFNA5-associated hearing loss represents a mechanism of gain-of-function.展开更多
受体型蛋白酪氨酸磷酸酶Q(Receptor type protein tyrosine phosphatase Q,PTPRQ)作为一种蛋白酪氨酸磷酸酶,能催化不同的底物,参与多种细胞内的功能。PTPRQ基因突变可导致常染色体隐性和显性非综合征性耳聋DFNB84A型和DFNA73型耳聋的发...受体型蛋白酪氨酸磷酸酶Q(Receptor type protein tyrosine phosphatase Q,PTPRQ)作为一种蛋白酪氨酸磷酸酶,能催化不同的底物,参与多种细胞内的功能。PTPRQ基因突变可导致常染色体隐性和显性非综合征性耳聋DFNB84A型和DFNA73型耳聋的发生,两型耳聋的临床表型差异提示了其致病机制的不同。在内耳,PTPRQ主要位于前庭及耳蜗毛细胞纤毛基底部,参与耳蜗毛细胞纤毛束的成熟,对维持纤毛的形态和功能具有重要作用。目前世界上报道的与PTPRQ突变相关的耳聋家系有14个,多数隐性突变是因截短或缺失而影响了PTPRQ的酶结构域的功能,但是PTPRQ的显性突变致病机理仍不清楚。有关该基因显、隐性突变致病机制的更深入研究可为相关病例的针对性干预提供理论依据。展开更多
文摘Q型蛋白酪氨酸磷酸酶受体(Receptor type protein tyrosine phosphatase Q,PTPRQ)是Ⅲ型酪氨酸磷酸酶受体家族的成员,具有磷酸酪氨酸磷酸酶和磷脂酰肌醇磷酸酶活性,可调节细胞的增殖、凋亡、分化等多种细胞内生理过程。在内耳方面,PTPRQ被认为是一种耳聋基因,主要参与耳蜗和前庭毛细胞的发育及成熟。研究发现,PTPRQ基因突变可导致两种非综合征性遗传性耳聋,包括DFNB84A型常染色体隐性耳聋和DFNA73型常染色体显性耳聋,两种耳聋的临床表型差异很大,这提示了其致病机制的不同。既往研究报道了多个耳聋家系与PTPRQ基因突变相关,本文对此做一综述,有助于识别治疗耳聋相关疾病的新靶点,并为PTPRQ突变致病机理的进一步研究提供理论参考。
基金This study was supported by a grant from the Jiangsu Health Administration，by a research grant award from the National Natural Science Foundation of China，by a grant from the Research Special Fund for Public Welfare Industry of Health,Ministry of Health of China
文摘Background： Nonsyndrornic hearing loss （NSHL） is highly heterogeneous, in which more than 90 causative genes have currently been identified. DFNA5 is one of the deathess genes that known to cause autosomal dominant NSHL. Until date, only five DFN.45 mutations have been described in eight families worldwide. In this study, we reported the identification of a novel pathogenic mutation causing DFNA5 deafness in a five-generation Chinese family. Methods： Alter detailed clinical evaluations of this family, the genomic DNA of three affected individuals was selected for targeted exome sequencing of 101 known deafness genes, as well as mitochondrial DNA and microRNA regions. Co-segregation analysis between the hearing loss and the candidate variant was confirmed in available family members by direct polymerase chain reaction （PCR）-Sanger sequencing. Real-time PCR （RT-PCR） was pertormed to investigate the potential effect of the pathogenic mutation on messenger RNA splicing. Results： Clinical evaluations revealed a similar deafness phenotype in this family to that of previously reported DFNA5 families with autosomal dominant, late-onset bearing loss. Molecular analysis identified a novel splice site mutation in DFNA5 intron 8 （IVSS＋ 1 delG）. The mutation segregated with the hearing loss of the family and was absent in 120 unrelated control DNA samples of Chinese origin. RT-PCR showed skipping of exon 8 in the mutant transcript. Conclusions： We identified a novel DFNA5 mutation IVS8＋1 delG in a Chinese family which led to skipping ofexon 8. This is the sixth DFNA5 mutation relates to hearing loss and the second one in DFNA5 intron 8. Our findings provide further support to the hypothesis that the DFNA5-associated hearing loss represents a mechanism of gain-of-function.
文摘受体型蛋白酪氨酸磷酸酶Q(Receptor type protein tyrosine phosphatase Q,PTPRQ)作为一种蛋白酪氨酸磷酸酶,能催化不同的底物,参与多种细胞内的功能。PTPRQ基因突变可导致常染色体隐性和显性非综合征性耳聋DFNB84A型和DFNA73型耳聋的发生,两型耳聋的临床表型差异提示了其致病机制的不同。在内耳,PTPRQ主要位于前庭及耳蜗毛细胞纤毛基底部,参与耳蜗毛细胞纤毛束的成熟,对维持纤毛的形态和功能具有重要作用。目前世界上报道的与PTPRQ突变相关的耳聋家系有14个,多数隐性突变是因截短或缺失而影响了PTPRQ的酶结构域的功能,但是PTPRQ的显性突变致病机理仍不清楚。有关该基因显、隐性突变致病机制的更深入研究可为相关病例的针对性干预提供理论依据。
