DFNB1 locus has been linked to a nonsyndromic “invisible disability” called congenital sensorineural hearing loss and deafness. Mutations of GJB2 and GJB6 genes are associated with deafness at the DFNB1 locus. The d...DFNB1 locus has been linked to a nonsyndromic “invisible disability” called congenital sensorineural hearing loss and deafness. Mutations of GJB2 and GJB6 genes are associated with deafness at the DFNB1 locus. The diagnosis of DFNB1 is made with molecular genetic testing. DNA-based testing can be used both prenatally and postnatally. Purpose: to get evidence for implementation of newborn hearing screening programs at national level;to use the molecular testing of children at risk for confirmation of diagnosis and early intervention. OAEs and ABR were performed for 4303 newborns. Audiologic evaluation of 38 children suspected of having hearing loss was performed too. Physical examinations and family history were used to get information about congenital deafness. DNA from blood samples was isolated, and two PCR multiplex assays were developed to detect DFNB1 mutations. Only 23 newborns were screened positive. Newborns were referred to audiologic evaluation, genetic counseling and testing for the etiologic diagnosis. Physical examination revealed no other abnormal findings. GJB2 mutations were detected in 36.03% of patients, and all of them have 35delG mutation. None of them was found to have GJB6 mutations. Our results suggested that molecular testing was an accurate method of early determining cause of congenital hearing loss and helped us to exclude GJB6 gene from the routine hearing screening protocol.展开更多
Gene therapy has shown promise for treating sensorineural hearing loss, supported by numerous successful preclinical studies. From the perspective of translation to humans, researchers have focused more on the genetic...Gene therapy has shown promise for treating sensorineural hearing loss, supported by numerous successful preclinical studies. From the perspective of translation to humans, researchers have focused more on the genetic causes of profound sensorineural hearing loss, where the sensory epithelium remains viable and intact for a considerable time after birth in humans. A key human deafness gene that best fits such a context is OTOF (GenBank AF183185.1), of which protein products, otoferlin, is essential for synaptic exocytosis and vesicle replenishment at the inner hair cell level in the cochlea.展开更多
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 The DFNB1 locus, which contains the gap junction beta-2 （GJB2） and gap junction beta-6 （GJB6） genes, plays a key role in the nonsyndromic and sporadic hearing impairment. Mutations of DFNB1 result in au...Background The DFNB1 locus, which contains the gap junction beta-2 （GJB2） and gap junction beta-6 （GJB6） genes, plays a key role in the nonsyndromic and sporadic hearing impairment. Mutations of DFNB1 result in autosomaJ recessive nonsyndromic hearing impairment （ARNSHI）. Previous researches have identified mutations in GJB2 and GJB6, but single nucleotide polymorphisms （SNPs） of DFNB1 locus have not been studied. So we chose five SNPs to evaluate whether there is difference between deafness people and normal-hearing people in Han Chinese. Methods Five SNPs in the DFNB1 region were examined using a case-control association study between cases with sporadic hearing impairment and controls with normal hearing. The HWEsoft and SHEsis softwares were used to analyze the results. Results Single-locus association analysis showed a positive association for three SNPs： rs9315400, rs2274084 and 235delC. When we compared the distributions of the haplotypes, we also found significant differences between cases and controls in the haplotype combination of rs2274084 and rs2274083 （Х^2=12.978, df=3, global P=0.004719）. Conclusions The haplotypes composed of rs2274084 and rs2274083 suggested that C-C may be a risk haplotype for the sporadic hearing impairment while T-T may be protective against hearing impairment. From that point of view, we can conclude that the SNPs of DFNB1 locus also plays an important role in sporadic hearing impairment cases.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
Otoancorin(OTOA)is a glycosylphosphatidylinositol(GPI)-anchored protein mediating the attachment of the tectorial membrane(TM)to the spiral limbus(SL)in the inner ear.Homozygous or compound heterozygous mutations in O...Otoancorin(OTOA)is a glycosylphosphatidylinositol(GPI)-anchored protein mediating the attachment of the tectorial membrane(TM)to the spiral limbus(SL)in the inner ear.Homozygous or compound heterozygous mutations in OTOA cause autosomal recessive deafness(DFNB22).We performed short-read exome sequencing(SRS)in a 10-monthold boy with sensorineural hearing loss,identifying a potential p.Glu787*variant in OTOA.Interestingly,this variant is common among normal-hearing individuals,leading us to question its pathogenic potential.展开更多
文摘DFNB1 locus has been linked to a nonsyndromic “invisible disability” called congenital sensorineural hearing loss and deafness. Mutations of GJB2 and GJB6 genes are associated with deafness at the DFNB1 locus. The diagnosis of DFNB1 is made with molecular genetic testing. DNA-based testing can be used both prenatally and postnatally. Purpose: to get evidence for implementation of newborn hearing screening programs at national level;to use the molecular testing of children at risk for confirmation of diagnosis and early intervention. OAEs and ABR were performed for 4303 newborns. Audiologic evaluation of 38 children suspected of having hearing loss was performed too. Physical examinations and family history were used to get information about congenital deafness. DNA from blood samples was isolated, and two PCR multiplex assays were developed to detect DFNB1 mutations. Only 23 newborns were screened positive. Newborns were referred to audiologic evaluation, genetic counseling and testing for the etiologic diagnosis. Physical examination revealed no other abnormal findings. GJB2 mutations were detected in 36.03% of patients, and all of them have 35delG mutation. None of them was found to have GJB6 mutations. Our results suggested that molecular testing was an accurate method of early determining cause of congenital hearing loss and helped us to exclude GJB6 gene from the routine hearing screening protocol.
基金supported by the Basic Science Research Program through the National Research Foundation of Korea,funded by the Ministry of Education,South Korea(No.2021R1A2C2092038 to B.Y.C.,2022R1I1A3072036 to E.Y.)Bio Core Facility center program through the NRF(No.2022M3A9G1014007 to B.Y.C.)+2 种基金also by the Basic Research Laboratory program through the NRF,funded by the Ministry of Science&ICT(MSIT)(No.RS-2023-0021971031482092640001 to B.Y.C.)the Technology Innovation Program(No.K_G012002572001 to B.Y.C.)funded by the Korean Ministry of TradeIndustry and Energy.This study is also funded by the Seoul National University Bundang Hospital intramural research fund(No.16-2020-0009,16-2022-0005,13-2023-0002,16-2023-0002,18-2023-0004,and 13-2024-0004 to B.Y.C.).
文摘Gene therapy has shown promise for treating sensorineural hearing loss, supported by numerous successful preclinical studies. From the perspective of translation to humans, researchers have focused more on the genetic causes of profound sensorineural hearing loss, where the sensory epithelium remains viable and intact for a considerable time after birth in humans. A key human deafness gene that best fits such a context is OTOF (GenBank AF183185.1), of which protein products, otoferlin, is essential for synaptic exocytosis and vesicle replenishment at the inner hair cell level in the cochlea.
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。
文摘Background The DFNB1 locus, which contains the gap junction beta-2 （GJB2） and gap junction beta-6 （GJB6） genes, plays a key role in the nonsyndromic and sporadic hearing impairment. Mutations of DFNB1 result in autosomaJ recessive nonsyndromic hearing impairment （ARNSHI）. Previous researches have identified mutations in GJB2 and GJB6, but single nucleotide polymorphisms （SNPs） of DFNB1 locus have not been studied. So we chose five SNPs to evaluate whether there is difference between deafness people and normal-hearing people in Han Chinese. Methods Five SNPs in the DFNB1 region were examined using a case-control association study between cases with sporadic hearing impairment and controls with normal hearing. The HWEsoft and SHEsis softwares were used to analyze the results. Results Single-locus association analysis showed a positive association for three SNPs： rs9315400, rs2274084 and 235delC. When we compared the distributions of the haplotypes, we also found significant differences between cases and controls in the haplotype combination of rs2274084 and rs2274083 （Х^2=12.978, df=3, global P=0.004719）. Conclusions The haplotypes composed of rs2274084 and rs2274083 suggested that C-C may be a risk haplotype for the sporadic hearing impairment while T-T may be protective against hearing impairment. From that point of view, we can conclude that the SNPs of DFNB1 locus also plays an important role in sporadic hearing impairment cases.
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。
基金supported by the National Research Foundation of Korea(NRF)grant funded by the Korean government(MSIT)(No.2021R1C1C1007980 to B.J.K.)Chungnam National University Sejong Hospital Research Fund,2022,and Chungnam National University(to B.J.K.)+6 种基金supported by the Basic Science Research Program through the NRF,funded by the Ministry of Education(No.2021R1A2C2092038 to B.Y.C.)Bio Core Facility Center program(No.NRF-2022M3A9G1014007 to B.Y.C.)the Basic Research Laboratory program through the NRF,funded by the Ministry of Education(No.RS-2023-0021971031482092640001 to B.Y.C.)the Technology Innovation Program(No.K_G012002572001 to B.Y.C.)funded By the Ministry of Trade,Industry&Energy(MOTIE,Korea)funded by SNUBH(Seoul National University Bundang Hospital)intramural research fund(No.13-2022-0010,02-2017-0060,16-2023-0002,13-2023-0002,16-2022-0005,13-2024-0004,and 13-2017-0013 to B.Y.C.)supported by the National Institute on Deafness and Other Communication Disorders(NIDCD)part of the US National Institutes of Health(No.R01DC018814 to S.P.).
文摘Otoancorin(OTOA)is a glycosylphosphatidylinositol(GPI)-anchored protein mediating the attachment of the tectorial membrane(TM)to the spiral limbus(SL)in the inner ear.Homozygous or compound heterozygous mutations in OTOA cause autosomal recessive deafness(DFNB22).We performed short-read exome sequencing(SRS)in a 10-monthold boy with sensorineural hearing loss,identifying a potential p.Glu787*variant in OTOA.Interestingly,this variant is common among normal-hearing individuals,leading us to question its pathogenic potential.
