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1.
Genes Genomics ; 45(2): 225-230, 2023 Feb.
Article in English | MEDLINE | ID: mdl-36630074

ABSTRACT

BACKGOUND: Hereditary hearing loss is one of the most common genetically heterogeneous defects in human. About 70% of hereditary hearing loss is defined as non-syndromic hearing loss showing loss of hearing ability without any other symptoms. Up to date, the identified genes associated with non-syndromic hearing loss are 128, including 52 genes for DFNA and 76 genes for DFNB. Because of high levels of heterogeneity, it is difficult to identify the causative factors for hearing loss using Sanger sequencing. OBJECTIVE: Our aim was to detect causative factors and investigate pathogenic mutations, which co-segregates within the candidate family. METHODS: We used Next Generation Sequencing technique to investigate whole-exome sequences of a Korean family with non-syndromic hereditary hearing loss. The family showed autosomal dominant inheritance pattern. RESULTS: We identified a novel missense variation, c.1978G > A in MYO7A gene, in the family with the autosomal dominant inheritance pattern. c.1978G > A produced Gly660Arg in the motor head domain of Myosin VIIA disrupt the ATP- and actin-binding motif function. CONCLUSION: This study is the first to report pathogenic mutations within MYO7A gene in Korean family and our data would facilitate diagnosing the primary cause of hereditary hearing loss in Korean.


Subject(s)
Deafness , Hearing Loss , Humans , Mutation, Missense , Hearing Loss/genetics , Deafness/genetics , Republic of Korea
2.
J Infect Chemother ; 27(2): 312-318, 2021 Feb.
Article in English | MEDLINE | ID: mdl-33223442

ABSTRACT

OBJECTIVES: To investigate whether initial blood urea nitrogen (BUN) and the neutrophil-to-lymphocyte ratio (NLR) in the emergency department (ED) are associated with mortality in elderly patients with genitourinary tract infections. METHODS: A total of 541 patients with genitourinary tract infections in 5 EDs between November 2016 and February 2017 were included and retrospectively reviewed. We assessed age, sex, comorbidities, vital signs, and initial laboratory results, including BUN, NLR and the SOFA criteria. The primary outcome was all-cause in-hospital mortality. RESULTS: The nonsurvivor group included 32 (5.9%) elderly patients, and the mean arterial pressure (MAP), NLR and BUN were significantly higher in this group than in the survivor group (p < 0.001, p = 0.003, p < 0.001). In multivariate analysis, MAP <70 mmHg, NLR ≥23.8 and BUN >28 mg/dl were shown to be independent risk factors for in-hospital mortality (OR 3.62, OR 2.51, OR 2.76: p = 0.002, p = 0.033, p = 0.038, respectively). Additionally, NLR ≥23.8 and BUN >28 were shown to be independent risk factors for mortality in admitted elderly with complicated UTI (p = 0.030, p = 0.035). When BUN and NLR were combined with MAP, the area under the ROC curve (AUROC) value was 0.807 (0.771-0.839) for the prediction of mortality, the sensitivity was 87.5% (95% CI 71.0-96.5), and the specificity was 61.3% (95% CI 56.9-65.5%). CONCLUSION: The initial BUN and NLR values with the MAP were good predictors associated with all-cause in-hospital mortality among elderly genitourinary tract infections visiting the ED.


Subject(s)
Lymphocytes , Neutrophils , Aged , Blood Urea Nitrogen , Humans , Prognosis , ROC Curve , Retrospective Studies
3.
Gene ; 627: 233-238, 2017 Sep 05.
Article in English | MEDLINE | ID: mdl-28647561

ABSTRACT

Hereditary hearing loss (HHL) is a common genetically heterogeneous disorder, which follows Mendelian inheritance in humans. Because of this heterogeneity, the identification of the causative gene of HHL by linkage analysis or Sanger sequencing have shown economic and temporal limitations. With recent advances in next-generation sequencing (NGS) techniques, rapid identification of a causative gene via massively parallel sequencing is now possible. We recruited a Korean family with three generations exhibiting autosomal dominant inheritance of hearing loss (HL), and the clinical information about this family revealed that there are no other symptoms accompanied with HL. To identify a causative mutation of HL in this family, we performed whole-exome sequencing of 4 family members, 3 affected and an unaffected. As the result, A novel splicing mutation, c.763+1G>T, in the solute carrier family 17, member 8 (SLC17A8) gene was identified in the patients, and the genotypes of the mutation were co-segregated with the phenotype of HL. Additionally, this mutation was not detected in 100 Koreans with normal hearing. Via NGS, we detected a novel splicing mutation that might influence the hearing ability within the patients with autosomal dominant non-syndromic HL. Our data suggests that this technique is a powerful tool to discover causative genetic factors of HL and facilitate diagnoses of the primary cause of HHL.


Subject(s)
Hearing Loss/genetics , Mutation , RNA Splicing , Vesicular Glutamate Transport Proteins/genetics , Adult , Aged , Exome , Female , Humans , Male , Pedigree , Republic of Korea
4.
Genes Genet Syst ; 91(5): 289-292, 2017 Apr 04.
Article in English | MEDLINE | ID: mdl-28003573

ABSTRACT

Hair cells in the cochlea display highly regulated actin polymerization, which is mediated by the human diaphanous-related formin 1 gene (DIAPH1; also called DFNA1, DIA1). DFNA1, the first type of autosomal dominant nonsyndromic hearing loss (ADNSHL), is known to be associated with mutations in DIAPH1. However, no genetic study of DFNA1 in Koreans with hearing loss has yet been reported. A 51-year-old patient in a Korean family with ADNSHL was examined by pure-tone audiometry, and genetic analysis of DIAPH1 was performed. A novel variant, p.I530S (c.1589T > G), was identified in the DIAPH1 gene, and the mutation was located in the highly conserved coiled-coil domain of the DIA1 protein, where an amino acid substitution was predicted to change the domain structure. Further functional investigations will provide more information to help us understand the role of DIAPH1 in maintenance of hair cell function in the auditory pathway.


Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Hearing Loss, Sensorineural/genetics , Mutation, Missense , Adaptor Proteins, Signal Transducing/metabolism , Amino Acid Sequence , Amino Acid Substitution , Base Sequence , Formins , Hearing Loss, Sensorineural/metabolism , Heredity , Humans , Male , Middle Aged , Pedigree
5.
Gene ; 591(1): 177-182, 2016 Oct 10.
Article in English | MEDLINE | ID: mdl-27393652

ABSTRACT

BACKGROUND: Myosin is a key protein involved in regulating the shape and motility of cells. The MYH9 and MYH14 genes, which encode non-muscle myosin heavy chain IIA (NMMHC II-A) and IIC (NMMHC II-C), respectively, are expressed in the inner ear. These myosin genes are known to be associated with autosomal dominant non-syndromic hearing loss (ADNSHL); however, genetic studies in patients with ADNSHL in Korea have rarely been reported. METHODS: We analyzed the MYH9 and MYH14 genes in 75 Korean patients with ADNSHL. RESULTS: We identified 4 possible pathogenic variants: a novel variant p.F1303L and 2 previously reported variants (p.R1730C and p.R1785C) in the MYH9 gene, and a novel variant p.A1868T in the MYH14 gene. All the variants were located in the myosin tail domain, which is essential for the interaction of myosin with actin. These variants were predicted to be possibly pathogenic by functional prediction tools and were absent in 100 unrelated normal controls. CONCLUSION: These results suggest that all the variants identified in this study have a strong potential to affect the structural stability and/or function of non-muscle myosin in the inner ear, which might lead to ADNSHL. This study establishes the link between the genotype and development of ADNSHL and contributes to the establishment of Korean database for hereditary hearing loss.


Subject(s)
Genetic Association Studies , Genetic Predisposition to Disease , Hearing Loss, Sensorineural/genetics , Myosin Heavy Chains/genetics , Amino Acid Sequence , Base Sequence , DNA Mutational Analysis , Female , Humans , Male , Mutation, Missense/genetics , Myosin Heavy Chains/chemistry , Pedigree , Republic of Korea
6.
Clin Exp Otorhinolaryngol ; 9(1): 21-6, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26976022

ABSTRACT

OBJECTIVES: Bone-anchored hearing aids (BAHA) occasionally cause soft tissue problems due to abutment. Because Sophono does not have abutment penetrating skin, it is thought that Sophono has no soft tissue problem relating to abutment. On the other hand, transcutaneous device's output is reported to be 10 to 15 dB lower than percutaneous device. Therefore, in this study, Sophono and BAHA were compared to each other from surgical and audiological points of view. METHODS: We retrospectively reviewed the medical records of 9 Sophono patients and 10 BAHA patients. In BAHA cases, single vertical incision without skin thinning technique was done. We compared Sophono to BAHA by operation time, wound healing time, postoperative complications, postoperative hearing gain after switch on, and postoperative air-bone gap. RESULTS: The mean operation time was 60 minutes for Sophono and 25 minutes for BAHA. The wound healing time was 14 days for Sophono and 28 days for BAHA. No major intraoperative complication was observed. Skin problem was not observed in the 2 devices for the follow-up period. Postoperative hearing gain of bilateral aural atresia patients was 39.4 dB for BAHA (n=4) and 25.5 dB for Sophono (n=5). However, the difference was not statistically significant. In all patients included in this study, the difference of air-bone gap between two groups was 16.6 dB at 0.5 kHz and 18.2 dB at 4 kHz. BAHA was statistically significantly better than Sophono. CONCLUSION: Considering the audiologic outcome, BAHA users were thought to have more audiologic benefit than Sophono users. However, Sophono had advantages over BAHA with abutment in cosmetic outcome. Sophono needed no daily skin maintenance and soft tissue complication due to abutment would not happen in Sophono. Therefore, a full explanation about each device is necessary before deciding implantation.

7.
BMC Med Genet ; 17: 6, 2016 Jan 22.
Article in English | MEDLINE | ID: mdl-26797701

ABSTRACT

BACKGROUND: One of the causes of sensorineural hearing loss (SNHL) is degeneration of the inner hair cells in the organ of Corti in the cochlea. The SLC17A8 (solute carrier family 17, member 8) gene encodes vesicular glutamate transporter 3 (VGLUT3), and among its isoforms (VGLUT1-3), only VGLUT3 is expressed selectively in the inner hair cells (IHCs). VGLUT3 transports the neurotransmitter glutamate into the synaptic vesicles of the IHCs. Mutation of the SLC17A8 gene is reported to be associated with DFNA25 (deafness, autosomal dominant 25), an autosomal dominant non-syndromic hearing loss (ADNSHL) in humans. METHODS: In this study, we performed a genetic analysis of 87 unrelated Korean patients with ADNSHL to determine whether the SLC17A8 gene affects hearing ability in the Korean population. RESULTS: We found a novel heterozygous frameshift mutation, 2 non-synonymous variations, and a synonymous variation. The novel frameshift mutation, p.M206Nfs*4, in which methionine is changed to asparagine at amino acid position 206, resulted in a termination codon at amino acid position 209. This alteration is predicted to encode a truncated protein lacking transmembrane domains 5 to 12. This mutation is located in a highly conserved region in VGLUT3 across multiple amino acid alignments in different vertebrate species, but it was not detected in 100 unrelated controls who had normal hearing ability. The results from our study suggest that the p.M206Nfs*4 mutation in the SLC17A8 gene is likely a pathogenic mutation that causes ADNSHL. CONCLUSION: Our findings can facilitate the prediction of the primary cause of ADNSHL in Korean patients.


Subject(s)
Asian People/genetics , Hearing Loss, Sensorineural/genetics , Vesicular Glutamate Transport Proteins/genetics , Amino Acid Sequence , Case-Control Studies , Female , Frameshift Mutation , Genetic Testing , Genomics , Humans , Male , Middle Aged , Molecular Sequence Data , Mutation , Pedigree , Polymorphism, Restriction Fragment Length , Republic of Korea , Sequence Alignment , Sequence Analysis, DNA
8.
Open Biol ; 4(7)2014 Jul.
Article in English | MEDLINE | ID: mdl-25080041

ABSTRACT

Mutations in five unconventional myosin genes have been associated with genetic hearing loss (HL). These genes encode the motor proteins myosin IA, IIIA, VI, VIIA and XVA. To date, most mutations in myosin genes have been found in the Caucasian population. In addition, only a few functional studies have been performed on the previously reported myosin mutations. We performed screening and functional studies for mutations in the MYO1A and MYO6 genes in Korean cases of autosomal dominant non-syndromic HL. We identified four novel heterozygous mutations in MYO6. Three mutations (p.R825X, p.R991X and Q918fsX941) produce a premature truncation of the myosin VI protein. Another mutation, p.R205Q, was associated with diminished actin-activated ATPase activity and actin gliding velocity of myosin VI in an in vitro analysis. This finding is consistent with the results of protein modelling studies and corroborates the pathogenicity of this mutation in the MYO6 gene. One missense variant, p.R544W, was found in the MYO1A gene, and in silico analysis suggested that this variant has deleterious effects on protein function. This finding is consistent with the results of protein modelling studies and corroborates the pathogenic effect of this mutation in the MYO6 gene.


Subject(s)
Hearing Loss/genetics , Mutation , Myosin Heavy Chains/genetics , Myosin Type I/genetics , Actins/metabolism , Adenosine Triphosphatases/metabolism , Amino Acid Sequence , Female , Humans , Male , Models, Molecular , Molecular Sequence Data , Mutation, Missense , Myosin Heavy Chains/analysis , Myosin Heavy Chains/metabolism , Myosin Type I/analysis , Myosin Type I/metabolism , Pedigree , Protein Conformation
9.
PLoS One ; 9(4): e95646, 2014.
Article in English | MEDLINE | ID: mdl-24752540

ABSTRACT

Tight junctions (TJs) are essential components of eukaryotic cells, and serve as paracellular barriers and zippers between adjacent tissues. TJs are critical for normal functioning of the organ of Corti, a part of the inner ear that causes loss of sensorineural hearing when damaged. To investigate the relation between genes involved in TJ function and hereditary loss of sensorineural hearing in the Korean population, we selected the TJP2 and CLDN14 genes as candidates for gene screening of 135 Korean individuals. The TJP2 gene, mutation of which causes autosomal dominant non-syndromic hearing loss (ADNSHL), lies at the DFNA51 locus on chromosome 9. The CLDN14 gene, mutation of which causes autosomal recessive non-syndromic hearing loss (ARNSHL), lies at the DFNB29 locus on chromosome 21. In the present study, we conducted genetic analyses of the TJP2 and CLDN14 genes in 87 unrelated patients with ADNSHL and 48 unrelated patients with either ARNSHL or potentially sporadic hearing loss. We identified two pathogenic variations, c.334G>A (p.A112T) and c.3562A>G (p.T1188A), and ten single nucleotide polymorphisms (SNPs) in the TJP2 gene. We found eight non-pathogenic variations in the CLDN14 gene. These findings indicate that, whereas mutation of the TJP2 gene might cause ADNSHL, CLDN14 is not a major causative gene for ARNSHL in the Korean population studied. Our findings may improve the understanding of the genetic cause of non-syndromic hearing loss in the Korean population.


Subject(s)
Asian People/genetics , Genetic Predisposition to Disease , Tight Junctions/genetics , Amino Acid Sequence , Base Sequence , Claudins/genetics , Deafness/genetics , Humans , Models, Molecular , Molecular Sequence Data , Polymorphism, Single Nucleotide/genetics , Protein Structure, Tertiary , Zonula Occludens-2 Protein/chemistry , Zonula Occludens-2 Protein/genetics
10.
BMC Med Genet ; 15: 46, 2014 Apr 28.
Article in English | MEDLINE | ID: mdl-24767429

ABSTRACT

BACKGROUND: Patient genetic heterogeneity renders it difficult to discover disease-cause genes. Whole-exome sequencing is a powerful new strategy that can be used to this end. The purpose of the present study was to identify a hitherto unknown mutation causing autosomal recessive nonsyndromic hearing loss (ARNSHL) in Korean families. METHODS: We performed whole-exome sequencing in 16 individuals from 13 unrelated small families with ARNSHL. After filtering out population-specific polymorphisms, we focused on known deafness genes. Pathogenic effects of the detected mutations on protein structure or function were predicted via in silico analysis. RESULTS: We identified compound heterozygous CDH23 mutations in hearing-loss genes of two families. These include two previously reported pathological mutations, p.Pro240Leu and p.Glu1595Lys, as well as one novel mutation, p.Asn342Ser. The p.Pro240Leu mutation was found in both families. We also identified 26 non-synonymous variants in CDH23 coding exons from 16 hearing-loss patients and 30 Korean exomes. CONCLUSION: The present study is the first to show that CDH23 mutations cause hearing loss in Koreans. Although the precise contribution made by such mutations needs to be determined using a larger patient cohort, our data indicate that mutations in the CDH23 gene are one of the most important causes of non-syndromic hearing loss in East Asians. Further exome sequencing will identify common mutations or polymorphisms and contribute to the molecular diagnosis of, and development of new therapies for, hereditary hearing loss.


Subject(s)
Asian People/genetics , Cadherins/genetics , Exome , Hearing Loss/genetics , Mutation , Amino Acid Sequence , Audiometry , Cadherin Related Proteins , Cadherins/chemistry , Child, Preschool , DNA Mutational Analysis , Exons , Female , Hearing Loss/diagnosis , High-Throughput Nucleotide Sequencing , Humans , Infant , Male , Models, Molecular , Molecular Sequence Data , Myosins/genetics , Pedigree , Polymorphism, Genetic , Protein Conformation , Protein Interaction Domains and Motifs , Republic of Korea , Sequence Alignment
11.
Laryngoscope ; 124(5): E194-202, 2014 May.
Article in English | MEDLINE | ID: mdl-24338212

ABSTRACT

OBJECTIVES/HYPOTHESIS: Enlarged vestibular aqueduct (EVA) and hearing loss are known to be caused by SLC26A4 mutations, but large phenotypic variability exists among patients with biallelic SLC26A4 mutations. Intrafamilial phenotypic variability was analyzed in multiplex EVA families carrying biallelic SLC26A4 mutations to identify the contribution of SLC26A4 mutations and other genetic or environmental factors influencing the clinical manifestations. STUDY DESIGN: Retrospective case series. METHODS: Eleven multiplex Korean families with EVA and hearing loss that carry biallelic mutations of the SLC26A4 gene were included. Genetic analysis for SLC26A4 and other genes including FOXI1, FOXI1-DBD, and KCNJ10 was performed. The auditory and other phenotypes were compared among siblings with the same SLC26A4 mutations. RESULTS: The difference in the auditory phenotypes was identified between siblings in approximately half of the EVA families. Families with SLC26A4 mutations other than H723R homozygous mutations demonstrated more phenotypic variability, especially in those carrying IVS7-2A>G splice site mutation. Cochlear malformation was a consistent finding among siblings with the same SLC26A4 mutations. No mutation was identified in the FOXI1, FOXI1-DBD, and KCNJ10 genes in the tested families. CONCLUSIONS: The possibility of variability concerning auditory phenotype should be considered even within family members carrying the same SLC26A4 mutations when providing genetic counseling to multiplex EVA families. Mutations in the currently known genes associated with EVA other than SLC26A4 were not found to be responsible for the intrafamilial phenotypic variability. Modifier genes or environmental factors other than the currently known genes seem to play a role in the phenotypic expressions of EVA patients.


Subject(s)
Hearing Loss, Sensorineural/genetics , Hearing Loss/genetics , Membrane Transport Proteins/genetics , Vestibular Aqueduct/abnormalities , Adolescent , Adult , Alleles , Asian People/genetics , Audiometry, Pure-Tone , Child , Child, Preschool , Female , Genotype , Humans , Infant , Male , Mutation , Phenotype , Polymerase Chain Reaction , Republic of Korea , Retrospective Studies , Sulfate Transporters
12.
BMC Med Genet ; 14: 72, 2013 Jul 17.
Article in English | MEDLINE | ID: mdl-23865914

ABSTRACT

BACKGROUND: The genetic heterogeneity of hearing loss makes genetic diagnosis expensive and time consuming using available methods. Whole-exome sequencing has recently been introduced as an alternative approach to identifying causative mutations in Mendelian disorders. METHODS: To identify the hidden mutations that cause autosomal recessive nonsyndromic hearing loss (ARNSHL), we performed whole-exome sequencing of 13 unrelated Korean small families with ARNSHL who were negative for GJB2 or SLC26A4 mutations. RESULTS: We found two novel compound heterozygous mutations, IVS11 + 1 and p.R2146Q, of MYO15A in one (SR903 family) of the 13 families with ARNSHL. In addition to these causative mutations, 13 nonsynonymous variants, including variants with uncertain pathogenicity (SR285 family), were identified in the coding exons of MYO15A from Korean exomes. CONCLUSION: This is the first report of MYO15A mutations in an East Asian population. We suggest that close attention should be paid to this gene when performing genetic testing of patients with hearing loss in East Asia. The present results also indicate that whole-exome sequencing is a valuable method for comprehensive medical diagnosis of a genetically heterogeneous recessive disease, especially in small-sized families.


Subject(s)
Exome/genetics , Hearing Loss, Sensorineural/genetics , Myosins/genetics , Asian People/genetics , Base Sequence , Chromosome Aberrations , Connexin 26 , Connexins/genetics , Genes, Recessive , Genetic Testing , Genetic Variation , Humans , Membrane Transport Proteins/genetics , Mutation , Republic of Korea , Sequence Analysis, DNA , Sulfate Transporters
13.
Int J Pediatr Otorhinolaryngol ; 77(5): 833-7, 2013 May.
Article in English | MEDLINE | ID: mdl-23523376

ABSTRACT

OBJECTIVES: SLC26A4 (PDS) mutations are common cause of congenital hearing loss in East Asia. Hearing loss caused by PDS mutations tends to have delayed presentation; thus universal newborn hearing screening (UNHS) can be less effective in these patients. We examined the efficiency of newborn hearing screening test in patients with bi-allelic PDS mutations. METHODS: Forty-three patients with sensorineural hearing loss were recruited. Patients had an enlarged vestibular aqueduct and biallelic PDS mutations. Among them, newborn hearing screening test had been performed on 14. The remaining 29 patients did not undergo newborn hearing screening test. Another 15 patients without a PDS mutation but who had sensorineural hearing loss were also recruited as a comparison group. We reviewed the hearing loss history of the children using medical records and parent interviews. RESULTS: Among 14 patients with PDS mutation, four (28.6%) passed newborn hearing screening test in both ears and six (42.9%) passed in one ear. In contrast, only 2 of 15 (13.3%) children without a PDS mutation passed newborn hearing screening test bilaterally. The age at confirmation of bilateral hearing loss in bilateral "pass" patients with PDS mutation was 31.5 ± 17.9 months, which was significantly delayed compared to the age for bilateral "refer" children (1.75 ± 0.96 months) (p<0.05). CONCLUSION: The UNHS is not an accurate tool for predicting long-term hearing loss in patients with PDS mutations. We recommend that genetic screening be combined with UNHS, particularly in communities with a high prevalence of PDS mutations, to better identify children in need of early habilitation.


Subject(s)
Genetic Testing/methods , Hearing Loss, Sensorineural/diagnosis , Membrane Transport Proteins/genetics , Neonatal Screening/methods , Child , Child, Preschool , Female , Hearing Loss, Sensorineural/epidemiology , Hearing Loss, Sensorineural/genetics , Hearing Tests , Humans , Infant , Infant, Newborn , Male , Mutation , Prevalence , Retrospective Studies , Sulfate Transporters
14.
Biochem Biophys Res Commun ; 430(3): 1147-50, 2013 Jan 18.
Article in English | MEDLINE | ID: mdl-23246836

ABSTRACT

INTRODUCTION: Mutations in PDS (or SLC26A4) cause both Pendred syndrome (PS) and DFNB4, two autosomal recessive disorders that share hearing loss as a common feature. PS and DFNB4 are genetically homogeneous disorders caused by bi-allelic SLC26A4 mutations. Here, we report a novel synonymous mutation (c.1803G>A, p.Lys601Lys), that caused aberrant splicing in two Korean family members who were clinically considered to have DFNB4, along with congenital hearing loss and dilated vestibular aqueducts (DVA). METHODS: After extracting DNA from whole blood using standard procedures, the 21 exons and flanking introns of SLC26A4 were amplified with PCR. To evaluate the implication of a novel synonymous mutation (c.1803G>A), we used The Berkeley Drosophila Genome Project (BDGP) (http://www.fruitfly.org/) as a splice site prediction program and performed exon trapping analysis. RESULTS: In molecular analysis of the 21 exons of SCL26A4, we detected a known splicing mutation (c.919-2A>G, heterozygote) and a novel variant (c.1803G>A, heterozygote) in the patients (II-1 and II-2). According to in silico analysis, the novel variant (c.1803G>A) affects canonical splice donor nucleotide positioning. To define the transcript level effects of this novel 1803G>A variant, we performed exon trapping and confirmed that exon 16 is completely skipped in this variant type. CONCLUSION: We report a novel synonymous mutation (c.1803G>A) causing complete exon 16 skipping in the SLC26A4 gene in two Korean family members with hearing loss. This is the first case of a synonymous SNP (c.1803G>A) affecting vestibulocochlear organs through altering splicing accuracy by causing a complete skipping of exon 16. An important issue raised by this study is that synonymous mutations that have been previously ignored in clinical diagnoses must now be considered as potential pathogenic mutations.


Subject(s)
Exons/genetics , Goiter, Nodular/genetics , Hearing Loss, Sensorineural/genetics , Membrane Transport Proteins/genetics , Asian People/genetics , Child, Preschool , Female , Humans , Male , Mutation , Pedigree , Polymorphism, Single Nucleotide , Republic of Korea , Sulfate Transporters
15.
PLoS One ; 7(8): e42463, 2012.
Article in English | MEDLINE | ID: mdl-22879993

ABSTRACT

Hearing loss, which is genetically heterogeneous, can be caused by mutations in the mitochondrial DNA (mtDNA). The A1555G mutation of the 12S ribosomal RNA (rRNA) gene in the mtDNA has been associated with both aminoglycoside-induced and non-syndromic hearing loss in many ethnic populations. Here, we report for the first time the clinical and genetic characterization of nine Korean pedigrees with aminoglycoside-induced and non-syndromic hearing loss. These Korean families carry in the A1555G mutation of 12S rRNA gene and exhibit variable penetrance and expressivity of hearing loss. Specifically, the penetrance of hearing loss in these families ranged between 28.6% and 75%, with an average of 60.8%. These results were higher than the 29.8% penetrance that was previously reported in a Chinese population but similar to the 65.4% and 54.1% penetrance observed in a large Arab-Israeli population and nineteen Spanish pedigrees, respectively. The mutational analysis of the complete mtDNA genome in these families showed that the haplogroups of the Korean population, which belongs to the eastern Asian population, were similar to those of the Chinese population but different from the Spanish population, which belongs to the European-Caucasian population. The mtDNA variants that may act as modifier factors were also found to be similar to the Chinese population. Although the mtDNA haplogroups and variants were similar to the eastern Asian population, we did find some differing phenotypes, although some subjects had the same variants. This result suggests that both the ethnic background and environmental factors lead to a variable phenotype of the A1555G mutation.


Subject(s)
DNA, Mitochondrial/genetics , Genetic Predisposition to Disease , Hearing Loss/genetics , Mutation/genetics , RNA, Ribosomal/genetics , Adult , Aged , Audiometry, Pure-Tone , Base Sequence , Connexin 26 , Connexins/genetics , DNA Mutational Analysis , Family , Female , Genome, Mitochondrial/genetics , Haplotypes/genetics , Humans , Male , Middle Aged , Mitochondrial Proteins/genetics , Molecular Sequence Data , Pedigree , Phenotype , Republic of Korea , tRNA Methyltransferases/genetics
16.
Clin Exp Otorhinolaryngol ; 5 Suppl 1: S10-3, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22701767

ABSTRACT

OBJECTIVES: Genetic hearing loss is highly heterogeneous and more than 100 genes are predicted to cause this disorder in humans. In spite of this large genetic heterogeneity, mutations in SLC26A4 and GJB2 genes are primarily responsible for the major etiologies of genetic hearing loss among Koreans. The purpose of this study is to investigate the genetic cause of deafness in Korean cochlear implantees by performing a genetic screening of the SLC26A4 and GJB2 genes. METHODS: The study cohort included 421 unrelated Korean patients with sensorineural hearing loss (SNHL) and who had received cochlear implants (CI) at Soree Ear Clinic from July 2002 to December 2010. Among 421 CI patients, we studied 230 cases who had received the genetic screening for SLC26A4 or GJB2 genes. Written informed consent was obtained from all participants. All patients had severe to profound, bilateral hearing loss. For 56 patients who showed enlarged vestibular aqueduct on their computed tomography (CT) scan, we analyzed SLC26A4. For 174 CT negative patients, GJB2 gene was sequenced. RESULTS: For the 56 SLC26A4 patients, 32 (57.1%) had two pathogenic recessive mutations in SLC26A4. A single recessive SLC26A4 mutation was identified in 14 patients (25%). H723R and IVS7-2A>G were the most commonly found mutations, accounting for 60.3% (47/78) and 30.8% (24/78) of the mutated alleles, respectively. For the 174 GJB2 patients, 20 patients (11.5%) had two pathogenic recessive mutations in GJB2. 235delC was the most common mutation, accounting for 43.0% (31/72) of mutant alleles. CONCLUSION: The two major genes, SLC26A4 and GJB2, contribute major causes of deafness in CI patients. Continuous studies are needed to identify new genes that can cause hearing loss to Korean CI patients.

17.
J Mol Med (Berl) ; 90(11): 1321-1331, 2012 Nov.
Article in English | MEDLINE | ID: mdl-22610276

ABSTRACT

Mutations in COCH have been associated with autosomal dominant nonsyndromic hearing loss (DFNA9) and are frequently accompanied by vestibular hypofunction. Here, we report identification of a novel missense mutation, p.F527C, located in the vWFA2 domain in members of a Korean family with late-onset and progressive hearing loss. To assess the molecular characteristics of this cochlin mutant, we constructed both wild-type and mutant cochlin constructs and transfected these into mammalian cell lines. Results of immunocytochemistry analysis demonstrated localization of the cochlin mutant in the endoplasmic reticulum/Golgi complex, whereas western blot analyses of cell lysates revealed that the mutant cochlin tends to form covalent complexes that are retained in the cell. Biochemical analyses of recombinant vWFA2 domain of cochlin carrying the p.F527C mutation revealed that the mutation increases propensity of the protein to form covalent disulfide-bonded dimers and affects the structural stability but not the collagen-affinity of the vWFA2 domain. We suggest that the instability of mutant cochlin is the major driving force for cochlin aggregation in the inner ear in DFNA9 patients carrying the COCH p.F527C mutation.


Subject(s)
Extracellular Matrix Proteins/genetics , Extracellular Matrix Proteins/physiology , Hearing Loss/genetics , Mutation , Adult , Amino Acid Sequence , Cell Line , Disulfides , Ear, Inner/metabolism , Endoplasmic Reticulum/metabolism , Female , Genes, Dominant , Golgi Apparatus/metabolism , Humans , Immunohistochemistry/methods , Male , Middle Aged , Molecular Sequence Data , Mutation, Missense , Pedigree , Protein Structure, Tertiary , Sequence Homology, Amino Acid
18.
Gene ; 492(1): 239-43, 2012 Jan 15.
Article in English | MEDLINE | ID: mdl-22037481

ABSTRACT

Mutations of the TECTA gene, which encodes alpha-tectorin, are associated with both dominant (DFNA8/A12) and recessive (DFNB 21) modes of inherited nonsyndromic sensorineural hearing loss, respectively. Although clinical data and genetic analysis for TECTA gene have been reported from different groups, there is no report that compound heterozygous mutations in the TECTA gene result in nonsyndromic sensorineural hearing loss. Here, we identified a missense mutation (p.C1691F) and a splicing mutation (c.6162+3insT), one in each TECTA allele, in the patient with hearing loss. Also, we demonstrated that the splicing mutation results in the abnormal skipping of an exon, which leads to a truncated protein as determined by exon-trapping analysis. To the best of our knowledge, this is the first report of an in vitro functional study of splice site mutations in the TECTA gene.


Subject(s)
Extracellular Matrix Proteins/genetics , Hearing Loss/genetics , Mutation , Child, Preschool , Female , GPI-Linked Proteins/genetics , Heterozygote , Humans , Pedigree
19.
Genes Genet Syst ; 86(2): 117-21, 2011.
Article in English | MEDLINE | ID: mdl-21670551

ABSTRACT

The linkage search for susceptibility loci using SNP markers in hereditary hearing loss has proven challenging due to genetic heterogeneity. We conducted a genome-wide linkage analysis using high-density SNP markers in two Korean families (families coded SD-J and SR-167) with autosomal dominant non-syndromic hearing loss (ADNSHL). Evidence was found of linkage at 8q24.13~q24.3 and 10p11.21~q22.2 (LOD 3.01) in the SD-J family. In the case of family SR-167, which had the most affected members, the parametric LOD score was low owing to the lack of power for linkage analysis. However, using non-parametric linkage analysis, it was possible to obtain significant evidence for linkage at 10q22.1~q23.31 (LOD 1.79; NPL 6.47, P<0.00001). There is an overlapping region with a significant LOD score between the SD-J and SR-167 families, which encompasses 4 cM at 10q22.1~22.2. Interestingly, the characteristics of hearing loss in both families were similar, and the haplotype within overlapping region was shared in the affected individuals of the two families. We performed direct sequencing of the candidate genes that are thought to be causing the condition, but no disease-causing mutations were identified.


Subject(s)
Chromosomes, Human, Pair 10/genetics , Genetic Predisposition to Disease/genetics , Hearing Loss/genetics , Polymorphism, Single Nucleotide/genetics , Computational Biology , DNA Mutational Analysis , Genes, Dominant , Genetic Linkage , Genomics/methods , Humans , Pedigree , Republic of Korea
20.
Mol Med ; 17(5-6): 550-6, 2011.
Article in English | MEDLINE | ID: mdl-21298213

ABSTRACT

Mutations in the gap junction ß2 (GJB2) gene, encoding the connexin26 (CX26) protein, are the most common cause of non-syndromic hearing loss (HL) in many populations. In the East Asian population, two variants, p.V27I (c.79G>A) and p.E114G (c.341G>A), are considered benign polymorphisms since these variants have been identified in both HL patients and normal hearing controls. However, some studies have postulated that homozygotes carrying both p.V27I and p.E114G variants could cause HL. To elucidate possible roles of these variants, we used in vitro approaches to directly assess the pathogenicity of four haplotypes generated by the two polymorphisms: VE (wild type), I*E (p.V27I variant only), VG* (p.E114G variant only), I*G* (both variants). In biochemical coupling assays, the gap junctions (GJs) composed of VG* and I*G* types displayed defective channel activities compared with those of VE wild types or I*E types, which showed normal channel activities. Interestingly, the defect in hemichannel activity was a bit less severe in I*G* type than VG* type, suggesting that I* variant (p.V27I) may compensate for the deleterious effect of G* variant (p.E114G) in hemichannel activities. Our population studies using 412 Korean individuals showed that I*G* type was detected at around 20% in both HL patients and normal controls, suggesting that I*G* type may not be a pathogenic polymorphism. In contrast, VG* type was very rare (3/824) and detected only in HL patients, suggesting that VG* homozygotes (VG*/VG*) or compound heterozygotes carrying VG* type with other mutations may cause HL.


Subject(s)
Connexins/genetics , Hearing Loss/genetics , Alleles , Asian People , Cell Line , Connexin 26 , Gap Junctions/genetics , Gap Junctions/metabolism , Genotype , Haplotypes/genetics , Humans , Linkage Disequilibrium/genetics , Polymorphism, Genetic/genetics
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