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ABSTRACT: Auditory neuropathy spectrum disorder (ANSD) is caused by dys-synchronous auditory neural response as a result of impairment of the functions of the auditory nerve or inner hair cells, or synapses between inner hair cells and the auditory nerve. To identify a causative gene causing ANSD in the Korean population, we conducted gene screening of the OTOF, DIAPH3, and PJVK genes in 19 unrelated Korean patients with ANSD. A novel nonsense mutation (p.Y1064X) and a known pathogenic mutation (p.R1939Q) of the OTOF gene were identified in a patient as compound heterozygote. Pedigree analysis for these mutations showed co-segregation of mutation genotype and the disease in the family, and it supported that the p.Y1064X might be a novel genetic cause of autosomal recessive ANSD. A novel missense variant p.K1017R (c.3050A>G) in the DIAPH3 gene was also identified in the heterozygous state. In contrast, no mutation was detected in the PJVK gene. These results indicate that no major causative gene has been reported to date in the Korean population and that pathogenic mutations in undiscovered candidate genes may have an effect on ANSD.
Gene 04/2013; · 2.34 Impact Factor
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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.
International journal of pediatric otorhinolaryngology 03/2013; · 0.85 Impact Factor
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Borum Sagong,
Jeong-In Baek,
Se-Kyung Oh,
Kyung Jin Na,
Jae Woong Bae,
Soo Young Choi,
Ji Yun Jeong,
Jae Young Choi,
Sang-Heun Lee,
Kyu-Yup Lee, Un-Kyung Kim
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ABSTRACT: Hearing loss (HL) is a congenital disease with a high prevalence, and patients with hearing loss need early diagnosis for treatment and prevention. The , , and genes have been reported as common causative genes of hearing loss in the Korean population and some mutations of these genes are the most common mutations associated with hearing loss. Accordingly, we developed a method for the simultaneous detection of seven mutations (c.235delC of , c.439A>G, c.919-2A>G, c.1149+3A>G, c.1229C>T, c.2168A>G of , and m.1555A>G of the gene) using multiplex SNaPshot minisequencing to enable rapid diagnosis of hereditary hearing loss. This method was confirmed in patients with hearing loss and used for genetic diagnosis of controls with normal hearing and neonates. We found that 4.06% of individuals with normal hearing and 4.32% of neonates were heterozygous carriers. In addition, we detected that an individual is heterozygous for two different mutations of and gene, respectively and one normal hearing showing the heteroplasmy of m.1555A>G. These genotypes corresponded to those determined by direct sequencing. Overall, we successfully developed a robust and cost-effective diagnosis method that detects common causative mutations of hearing loss in the Korean population. This method will be possible to detect up to 40% causative mutations associated with prelingual HL in the Korean population and serve as a useful genetic technique for diagnosis of hearing loss for patients, carriers, neonates, and fetuses.
PLoS ONE 01/2013; 8(3):e57237. · 4.09 Impact Factor
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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 SLC4A26, 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.
Biochemical and Biophysical Research Communications 12/2012; · 2.48 Impact Factor
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ABSTRACT: BACKGROUND: Carbonic anhydrases (CAs), which catalyze CO(2) hydration to bicarbonate and protons, have been suggested to regulate potassium homeostasis and endocochlear potential in the mammalian cochlea. Sixteen mammalian CA isozymes are currently known. To understand the specific roles of CA isozymes in the inner ear, a systematic survey was conducted to reveal temporal and spatial expression patterns of all 16 CA isozymes during inner ear development. RESULTS: Our quantitative RT-PCR results showed that different tissues express unique combinations of CA isozymes. During inner ear development, transcripts of four cytosolic isozymes (Car1, Car2, Car3, and Car13), two membrane-bound isozymes (Car12 and Car14), and two CA-related proteins (Car8 and Car11) were expressed at higher levels than other isozymes. Spatial expression patterns of these isozymes within developing inner ears were determined by in situ hybridization. Each isozyme showed a unique expression pattern during development. For example, Car12 and Car13 expression closely overlapped with Pendrin, an anion exchanger, while Car2 overlapped with Na-K-ATPase in type II and IV otic fibrocytes, suggesting functional relationships in the inner ear. CONCLUSIONS: The temporal and spatial expression patterns of each CA isozyme suggest unique and differential roles in inner ear development and function.
Developmental Dynamics 12/2012; · 2.54 Impact Factor
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ABSTRACT: BACKGROUND: Hereditary hearing loss is one of the most common heterogeneous disorders, and genetic variants that can cause hearing loss have been identified in over fifty genes. Most of these hearing loss genes have been detected using classical genetic methods, typically starting with linkage analysis in large families with hereditary hearing loss. However, these classical strategies are not well suited for mutation analysis in smaller families who have insufficient genetic information. METHODS: Eighty known hearing loss genes were selected and simultaneously sequenced by targeted next-generation sequencing (NGS) in 8 Korean families with autosomal dominant non-syndromic sensorineural hearing loss. RESULTS: Five mutations in known hearing loss genes, including 1 nonsense and 4 missense mutations, were identified in 5 different genes (ACTG1, MYO1F, DIAPH1, POU4F3 and EYA4), and the genotypes for these mutations were consistent with the autosomal dominant inheritance pattern of hearing loss in each family. No mutational hot-spots were revealed in these Korean families. CONCLUSION: Targeted NGS allowed for the detection of pathogenic mutations in affected individuals who were not candidates for classical genetic studies. This report is the first documenting the effective use of an NGS technique to detect pathogenic mutations that underlie hearing loss in an East Asian population. Using this NGS technique to establish a database of common mutations in Korean patients with hearing loss and further data accumulation will contribute to the early diagnosis and fundamental therapies for hereditary hearing loss.
Orphanet Journal of Rare Diseases 09/2012; 7(1):60. · 5.83 Impact Factor
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Molecular Biology Reports 09/2012; 39(9):9275. · 2.93 Impact Factor
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ABSTRACT: Pendred syndrome (PS) is an autosomal recessive disorder characterized by congenital bilateral sensorineural hearing loss, goiter, and incomplete iodide organification. Patients with PS also have structural anomalies of the inner ear such as enlarged vestibular aqueducts (EVA) and Mondini's malformation. The goiter, which is a major clinical manifestation of PS, usually develops around adolescence. PS is caused by biallelic mutations of the SLC26A4 gene, while nonsyndromic bilateral EVA is associated with zero or one SLC26A4 mutant allele. We report here a Korean family including a young female with PS who had goiter and progressive, fluctuating sensorineural hearing loss that could be partially recovered by oral steroid treatment. Genetic investigation revealed compound heterozygous mutations for p.R677AfsX11, a novel frameshift mutation, and p.H723R in the SLC26A4 gene. Our findings provide detailed information regarding the distribution of mutant alleles for PS and may serve as a foundation for studies to comprehend the genetic portion of syndromic hearing loss.
Gene 08/2012; 508(1):135-9. · 2.34 Impact Factor
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ABSTRACT: A number of genes responsible for hearing loss are related to ion recycling and homeostasis in the inner ear. Connexins (Cx26 encoded by GJB2, Cx31 encoded by GJB3 and Cx30 encoded by GJB6) are core components of gap junctions in the inner ear. Gap junctions are intercellular communication channels and important factors that are associated with hearing loss. To date, a molecular genetics study of GJB3 and GJB6 as a causative gene for hearing loss has not been performed in Korea. This study was therefore performed to elucidate the genetic characteristics of Korean patients with nonsyndromic sensorineural hearing loss and to determine the pathological mechanism of hearing loss by analyzing the intercellular communication function of Cx30 and Cx31 variants. Sequencing analysis of the GJB3 and GJB6 genes in our population revealed a total of nine variants, including four novel variants in the two genes. Three of the novel variants (Cx31-p.V27M, Cx31-p.V43M and Cx-30-p.I248V) and two previously reported variants (Cx31-p.V84I and Cx30-p.A40V) were selected for functional studies using a pathogenicity prediction program and assessed for whether the mutations were located in a conserved region of the protein. The results of biochemical and ionic coupling tests showed that both the Cx31-p.V27M and Cx31-p.V84I variants did not function normally when each was expressed as a heterozygote with the wild-type Cx31. This study demonstrated that two variants of Cx31 were pathogenic mutations with deleterious effect. This information will be valuable in understanding the pathogenic role of GJB3 and GJB6 mutations associated with hearing loss.
Biochimica et Biophysica Acta 05/2012; · 4.66 Impact Factor
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Hyun-Ju Cho,
Hong-Joon Park,
Maria Trexler,
Hanka Venselaar,
Kyu-Yup Lee,
Nahid G Robertson,
Jeong-In Baek,
Beom Sik Kang,
Cynthia C Morton,
Gert Vriend,
László Patthy, Un-Kyung Kim
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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.
Journal of Molecular Medicine 05/2012; 90(11):1321-31. · 4.67 Impact Factor
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ABSTRACT: Hereditary nonsyndromic hearing loss (NSHL) is a highly heterogeneous disorder in humans. Mutations of the transmembrane channel-like
(TMC1) gene have been identified as the genetic cause for both autosomal recessive (DFNB7/11) and autosomal dominant (DFNA36) nonsyndromic
hearing loss. To evaluate the spectrum and frequency of mutation(s) caused by TMC1 gene in the Korean population, we have performed sequencing analysis of the PCR products amplified from genomic DNA of each
proband in 193 unrelated families showing 30 autosomal dominant and 163 autosomal recessive inheritance patterns. As a result,
we identified eight different novel sequence variations for the first time in this study, respectively. However, none of these
showed co-segregation of phenotype in the families. Therefore, our study suggests that the TMC1 gene is not the cause of nonsyndromic hearing loss in the Korean population.
KeywordsNonsyndromic hearing loss–
TMC1
–Gene–Mutation–Polymorphism
Genes & genomics 04/2012; 33(2):205-207. · 0.44 Impact Factor
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ABSTRACT: Microsatellites, short tandem repeats, are useful markers for genetic analysis because of their high frequency of occurrence
over the genome, high information content due to variable repeat lengths, and ease of typing. To establish a panel of microsatellite
markers useful for genetic studies for hereditary hearing loss in the Korean population, the allele frequencies and heterozygosities
of 32 microsatellite markers in 172 unrelated Korean individuals were examined. The heterozygosity values for these markers
ranged from 48 to 87%. All the markers except D6S1038 and D14S1034 marker showed PIC values over 0.5. This indicates these
markers have a high degree of polymorphism and are randomly distributed in the Korean population. Therefore, the combinations
of these STR loci provide a powerful tool to find the candidate loci of a causative gens for non-syndromic hearing loss in
the Korean population.
Key wordsshort tandom repeat (STR)-heterozygosity-Korean
Genes & genomics 04/2012; 31(6):451-456. · 0.44 Impact Factor
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ABSTRACT: Umami is a pleasant savoury taste imparted by glutamate, a type of amino acid, and ribonucleotides, including inosinate and
guanylate, which occur naturally in many foods including meat, fish, vegetables and dairy products. A heterodimer of TAS1R1
and TAS1R3 is known to function as umami taste receptor in humans. To address the association between genetic polymorphism
of TAS1R1 / TAS1R3 genes and individual difference in umami taste sensitivity, we have examined the entire coding region of these genes using
PCR-mediated direct sequencing analysis. A total of 11 SNPs were identified from 98 unrelated Korean individuals and were
in Hardy-Weinberg Equilibrium. Four out of 11 SNPs were found in the exons and two of them were nonsynonymous ones. These
coding SNPs (cSNPs), p.A372T in TAS1R1 and p.C757R in TAS1R3 genes, were common in Koreans, so these will be useful resource for further studies to find a functional allele for individual
variation to umami taste sensitivity in our population.
KeywordsUmami taste-TAS1R1-TAS1R3-Genes-Single-nucleotide Polymorphims
Genes & genomics 04/2012; 32(2):111-113. · 0.44 Impact Factor
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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.
Gene 01/2012; 492(1):239-43. · 2.34 Impact Factor
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ABSTRACT: To date, 135 loci and 50 genes have been identified as causes of nonsyndromic hearing loss. Until recently, four loci (DFN2, DFN3, DFN4, and DFN6) had been implicated in nonsyndromic X-linked hearing loss; however, a new classification (DFNX1-5) has been proposed to reduce confusion in the terminology. The different types of nonsyndromic X-linked hearing loss demonstrate various clinical features in terms of the onset and progressiveness of hearing loss, pattern of audiogram, and the presence or absence of inner ear malformations. In addition to the POU3F4 gene, which was the first gene identified as causing nonsyndromic X-linked hearing loss, a second gene, PRPS1, has recently been identified to be the causative gene of DFNX1 (DFN2). This study reviews the new classification system, as well as the clinical features, molecular genetics, and developmental pathogenesis of different forms of nonsyndromic X-linked hearing loss.
Frontiers in bioscience (Elite edition) 01/2012; 4:924-33.
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Jae Woong Bae,
Dong-Bin Kim,
Jae Young Choi,
Hong-Joon Park,
Jong Dae Lee,
Dong Gu Hur,
Seung-Hyun Bae,
Da Jung Jung,
Sang Heun Lee, Un-Kyung Kim,
Kyu Yup Lee
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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.
PLoS ONE 01/2012; 7(8):e42463. · 4.09 Impact Factor
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ABSTRACT: Mutations in the neurofibromatosis type 2 (NF2) tumor-suppressor gene have been identified in not only NF2-related tumors but also sporadic vestibular schwannomas (VS). This study investigated the genetic and epigenetic alterations in tumors and blood from 30 Korean patients with sporadic VS and correlated these alterations with tumor behavior.
NF2 gene mutations were detected using PCR and direct DNA sequencing and three highly polymorphic microsatellite DNA markers were used to assess the loss of heterozygosity (LOH) from chromosome 22. Aberrant hypermethylation of the CpG island of the NF2 gene was also analyzed. The tumor size, the clinical growth index, and the proliferative activity assessed using the Ki-67 labeling index were evaluated. We found 18 mutations in 16 cases of 30 schwannomas (53%). The mutations included eight frameshift mutations, seven nonsense mutations, one in-frame deletion, one splicing donor site, and one missense mutation. Nine patients (30%) showed allelic loss. No patient had aberrant hypermethylation of the NF2 gene and correlation between NF2 genetic alterations and tumor behavior was not observed in this study.
The molecular genetic changes in sporadic VS identified here included mutations and allelic loss, but no aberrant hypermethylation of the NF2 gene was detected. In addition, no clear genotype/phenotype correlation was identified. Therefore, it is likely that other factors contribute to tumor formation and growth.
PLoS ONE 01/2012; 7(1):e30418. · 4.09 Impact Factor
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ABSTRACT: Most of the patients with enlarged vestibular aqueduct (EVA) experience sudden hearing deterioration, but the exact mechanism is unclear. We analyzed magnetic resonance (MR) images and the cellular components of endolymph obtained from the endolymphatic sac in patients with EVA, in order to demonstrate the cause of sudden hearing loss.
A total of 25 patients (50 ears) with EVA, who had severe to profound hearing loss, were included in this retrospective clinical study. MR examinations were performed by a 3.0-T MR system using an 8-channel sensitivity-encoding head coil. We analyzed endolymphatic fluid harvested from the endolymphatic sac during cochlear implantations in four patients.
The area of low signal intensity in the endolymphatic sac was observed on T2-weighted MR images for 15 of 50 ears. This area was observed more frequently in patients who experienced recent sudden hearing loss (10/12, 83%) than those with stable hearing (5/38, 13%)(Fisher's exact test, p<0.001). In addition, this area showed high signal intensity on fluid attenuated inversion recovery images. Cytologic analysis of the aspirated endolymph from the endolymphatic sac in the patients with this area revealed many erythrocytes.
Our data suggests that hemorrhage in the endolymphatic sac could be a cause of sudden hearing deterioration in patients with EVA.
International journal of pediatric otorhinolaryngology 09/2011; 75(12):1538-44. · 0.85 Impact Factor
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ABSTRACT: Hearing loss is a common communication disorder caused by various environmental and genetic factors. Hereditary hearing loss is very heterogeneous, and most of such cases involve sensorineural defects in the auditory pathway. There are currently 57 known autosomal dominant non-syndromic hearing loss (DFNA) loci, and the causative genes have been identified at 22 of these loci. In the present study, we performed a genome-wide linkage analysis in a Korean family segregating autosomal dominant hearing loss. We observed linkage on chromosome 1p34, and at this locus, we detected a novel mutation consisting of an 18 nucleotide deletion in exon 4 of the KCNQ4 gene, which encodes a voltage-gated potassium channel. We carried out a functional in vitro study to analyze the effects of this mutation (c.664_681del) along with two previously described KCNQ4 mutations, p.W276S and p.G285C. Although the c.664_681del mutation is located in the intercellular loop and the two previously described mutations, p.W276S and p.G285C, are located in the pore region, all mutants inhibit normal channel function by a dominant negative effect. Our analysis indicates that the intercellular loop is as significant as the pore region as a potential site of pathogenic effects on KCNQ4 channel function.
Biochimica et Biophysica Acta 04/2011; 1812(4):536-43. · 4.66 Impact Factor
