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1.
Diabetes Res Clin Pract ; 180: 109077, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34599972

RESUMO

AIMS: Obesity is the most common risk factor for type 2 diabetes. However, not all obese individuals develop diabetes. In the era of precision medicine, metabolomics may reveal the fundamental metabolic status of an individual. Our aim was to assess the association of metabolites with incident type 2 diabetes in obese individuals using Korean Genome and Epidemiology Cohort Study. METHODS: Using 12 years of metabolomic data from 2,580 individuals, we performed a metabolomic study to define metabolically healthy obesity in an obese population (n = 704) with incident type 2 diabetes. Cox proportional hazards regression model and survival analysis were performed adjusted for the traditional risk factors of type 2 diabetes. RESULTS: Our study revealed that spermine, acyl-alkyl phosphatidylcholines (C34:3, C36:3, C42:1), hydroxy sphingomyelin (C22:2, C14:1), and sphingomyelin (C16:0) were associated with incident type 2 diabetes in obese individuals after the adjustment for risk factors and correction of multiple comparisons by Bonferroni method. Five metabolites (except hydroxy sphingomyelin C14:1 and sphingomyelin C16:0) were also significantly associated with incident type 2 diabetes in lean individuals. CONCLUSIONS: This study highlights the need for defining metabolically healthy obesity based on serum metabolites and elucidates potential biomarkers for type 2 diabetes in an obese population.


Assuntos
Diabetes Mellitus Tipo 2 , Biomarcadores , Estudos de Coortes , Diabetes Mellitus Tipo 2/epidemiologia , Humanos , Metabolômica , Obesidade/complicações , Obesidade/epidemiologia , Fatores de Risco
2.
BMC Infect Dis ; 21(1): 1099, 2021 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-34702193

RESUMO

BACKGROUND: Pharmacokinetic-pharmacodynamic (PK/PD) targets of vancomycin therapy have been recognized for methicillin-resistant Staphylococcus aureus infections but not for other gram-positive bacterial infections. Therefore, we investigated whether vancomycin concentration targets such as the trough level and ratio of the area under the curve to minimum inhibitory concentration (AUC/MIC) are associated with the treatment outcome in enterococcal bacteremia. METHODS: A retrospective cohort analysis enrolled patients with bacteremia caused by vancomycin-susceptible Enterococcus faecium and Enterococcus faecalis who were treated with vancomycin from January 2007 to December 2017 at a tertiary hospital located in Seoul, South Korea. Patients without vancomycin concentrations were excluded from the study. The primary outcome was 28-day all-cause mortality. RESULTS: A total of 37 patients were enrolled-26 with E. faecium infection and 11 with E. faecalis infection. The 28-day all-cause mortality rate was 21.6 %. In univariate analysis, vancomycin trough level (≤ 15 µg/mL; p = 0.042), age (p = 0.044), and septic shock (p = 0.049) were associated with 28-day mortality but not AUC24/MIC (> 389; p = 0.479). In multivariate analysis, vancomycin trough concentration (≤ 15 µg/mL; p = 0.041) and younger age (p = 0.031) were associated with 28-day mortality in patients with enterococcal bacteremia. CONCLUSIONS: In this study, a vancomycin trough level of 15 µg/mL or lower was associated with 28-day mortality in enterococcal bacteremia. However, relatively large prospective studies are needed to examine the efficacy of vancomycin PK/PD parameters in patients with enterococcal bacteremia.


Assuntos
Bacteriemia , Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Antibacterianos/uso terapêutico , Bacteriemia/tratamento farmacológico , Enterococcus , Humanos , Testes de Sensibilidade Microbiana , Estudos Retrospectivos , Infecções Estafilocócicas/tratamento farmacológico , Resultado do Tratamento , Vancomicina/uso terapêutico
4.
Hum Genet ; 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34519870

RESUMO

Ski-slope hearing loss (HL), which refers to increased auditory threshold at high frequencies, is common in adults. However, genetic contributions to this post-lingual HL remain largely unknown. Here, we prospectively investigated deafness-associated and novel candidate genes causing ski-slope HL. We analyzed 192 families with post-lingual HL via gene panel and/or exome sequencing. With an overall molecular diagnostic rate of 35.4% (68/192) in post-lingual HL, ski-slope HL showed a lower diagnostic rate (30.7%) compared with other conditions (40.7%). In patients who showed HL onset before the age of 40, genetic diagnostic probability was significantly lower for ski-slope HL than for other conditions. Further analysis of 51 genetically undiagnosed patients in the ski-slope HL group identified three variants in delta-like ligand 1 (DLL1), a Notch ligand, which presented in vitro gain-of-function effects on Notch downstream signaling. In conclusion, genetic diagnostic rates in post-lingual HL varied according to audiogram patterns with age-of-onset as a confounding factor. DLL1 was identified as a candidate gene causing ski-slope HL.

5.
Hum Genet ; 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34529116

RESUMO

This phenotype-genotype study aimed to investigate the extent of audioprofile variability related to cochlin major domains and to identify potential ethnic-specific differences associated with COCH-related hearing loss. Eight Korean families (26 cases) were diagnosed with COCH-related hearing loss by exome sequencing. Audiometric test results were combined with those from nine published East Asian families (20 cases) and compared with those from 38 European-descent families (277 cases). Audioprofiles were created by grouping audiometric test results into age ranges by age at testing and then averaging hearing loss thresholds by frequency within age ranges. The functional impact of the identified variants was assessed in vitro by examining the intracellular trafficking, secretion, and cleavage of cochlin. In both East Asian and European-descent families segregating COCH-related hearing loss, deafness-associated variants in non-LCCL domains of cochlin were associated with hearing loss that was more severe earlier in life than hearing loss caused by variants in the LCCL domain. Consistent with this phenotypic difference, functional studies demonstrated distinct pathogenic mechanisms for COCH variants in a domain-dependent manner; specifically, a cytotoxic effect was observed for the p.Phe230Leu variant, which is located in the vWFA1 domain. No ethnic-specific differences in hearing loss progression were observed, except for those attributable to an overrepresentation of presymptomatic cases in the European-descent cohort.

6.
Int J Mol Sci ; 22(5)2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33801540

RESUMO

Potassium voltage-gated channel subfamily q member 4 (KCNQ4) is a voltage-gated potassium channel that plays essential roles in maintaining ion homeostasis and regulating hair cell membrane potential. Reduction of the activity of the KCNQ4 channel owing to genetic mutations is responsible for nonsyndromic hearing loss, a typically late-onset, initially high-frequency loss progressing over time. In addition, variants of KCNQ4 have also been associated with noise-induced hearing loss and age-related hearing loss. Therefore, the discovery of small compounds activating or potentiating KCNQ4 is an important strategy for the curative treatment of hearing loss. In this review, we updated the current concept of the physiological role of KCNQ4 in the inner ear and the pathologic mechanism underlying the role of KCNQ4 variants with regard to hearing loss. Finally, we focused on currently developed KCNQ4 activators and their pros and cons, paving the way for the future development of specific KCNQ4 activators as a remedy for hearing loss.


Assuntos
Perda Auditiva/patologia , Canais de Potássio KCNQ/genética , Mutação , Animais , Perda Auditiva/genética , Perda Auditiva/terapia , Humanos
8.
Hear Res ; 404: 108227, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33784549

RESUMO

Autosomal recessive nonsyndromic hearing loss 3 (DFNB3) mainly leads to congenital and severe-to-profound hearing impairment, which is caused by variants in MYO15A. However, audiological heterogeneity in patients with DFNB3 hinders precision medicine in hearing rehabilitation. Here, we aimed to elucidate the heterogeneity of the auditory phenotypes of MYO15A variants according to the affected domain and the feasibilities for acoustic stimulation. We conducted whole-exome sequencing for 10 unrelated individuals from seven multiplex families with DFNB3; 11 MYO15A variants, including the novel frameshift c.900delT (p.Pro301Argfs*143) and nonsense c.4879G > T (p.Glu1627*) variants, were identified. In seven probands, residual hearing at low frequencies was significantly higher in the groups with one or two N-terminal frameshift variants in trans conformation compared to that in the group without these variants. This is consistent with the 56 individuals from the previously published reports that carried a varying number of N-terminal truncating variants in MYO15A. In addition, patients with missense variants in the second FERM domain had better hearing at low frequencies than patients without these variants. Subsequently, acoustic stimulation provided by devices such as hearing aids or cochlear implants was feasible in patients with one or two N-terminal truncating variants or a second FERM missense variant. In conclusion, N-terminal or second FERM variants in MYO15A allow the practical use of acoustic stimulation through hearing aids or electroacoustic stimulation for aural rehabilitation.

9.
Front Med (Lausanne) ; 8: 637241, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33777980

RESUMO

Background: We investigated the effects of anthropometric, laboratory, and lifestyle factors on the development of non-alcoholic fatty liver disease (NAFLD) in a nationwide, population-based, 4-year retrospective cohort. Methods: The propensity score-matched study and control groups contained 1,474 subjects who had data in the Korean National Health Insurance Service-National Sample Cohort in 2009, 2011, and 2013. NAFLD was defined using medical records of a diagnosis confirmed by primary clinicians and meeting two previously validated fatty liver prediction models. Chronological changes in anthropometric variables, laboratory results, and lifestyle factors during two periods were compared between patient and control groups in order to find out parameters with consistent dynamics in pre-NAFLD stage which was defined as period just before the NAFLD development. Results: Among the 5 anthropometric, 10 laboratory, and 3 lifestyle factors, prominent chronological decremental changes in serum triglycerides were consistently observed during the pre-NAFLD stage, although the degrees of changes were more predominant in men (-9.46 mg/dL) than women (-5.98 mg/dL). Furthermore, weight and waist circumference changes during the pre-NAFLD stage were noticeable only in women (+0.36 kg and +0.9 cm for weight and waist circumference, respectively), which suggest gender difference in NAFLD. Conclusion: Early screening strategies for people with abrupt chronological changes in serum triglycerides to predict NAFLD development before the progression is recommended.

10.
Nutrition ; 83: 111090, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33418492

RESUMO

OBJECTIVES: This study aimed to investigate the potential of using changes in the plasma levels of trimethylamine N-oxide (TMAO), a gut microbiota-derived metabolite, as a biomarker in early Parkinson's disease (PD). METHODS: Plasma TMAO levels were measured in 85 patients with drug-naïve early stage PD and 20 healthy controls. A linear mixed model was used to assess longitudinal changes in levodopa-equivalent dose (LED) during follow-up (>2 y) in three tertile PD groups according to plasma TMAO levels. Additionally, a Cox regression analysis was performed to assess the effect of plasma TMAO levels on dementia conversion. RESULTS: Plasma TMAO levels of patients with PD were lower than those of healthy controls. A linear mixed model demonstrated that patients with PD and lower levels of TMAO (<4.75 µmol/L; i.e., lowest tertile group) exhibited faster increases in LED over time. The Cox regression model did not reveal that plasma TMAO level was associated with the risk for dementia conversion (P = 0.488). However, when we divided patients with PD into two subgroups according to bet cutoff TMAO level to maximize the log-rank statistics, the PD group with a low plasma TMAO level (<6.92 µmol/L) had a higher risk (with borderline statistical significance) for PD-dementia conversion than the group with a high TMAO level (hazard ratio: 7.565; 95% confidence interval, 1.004-57.019; P = 0.050). CONCLUSIONS: The results demonstrate that lower baseline plasma TMAO levels are associated with faster increases in LED and tend to increase the risk for PD-dementia conversion, suggesting the prognostic implications of TMAO in early stage PD.


Assuntos
Microbioma Gastrointestinal , Doença de Parkinson , Biomarcadores , Humanos , Metilaminas
12.
Sci Rep ; 10(1): 21398, 2020 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-33293655

RESUMO

Post-transplant malignancy (PTM) is a leading cause of premature mortality among kidney transplantation recipients. However, population-based cohort studies that cover incidence, mortality, and risk factors for PTM are rarely reported, especially in East Asia. We designed a retrospective cohort study using a national population-based database. A total of 9915 kidney recipients between 2003 and 2016 were included. During this period, 598 cases (6.0%) of de novo PTM occurred. The most common PTM was thyroid cancer (14.2%), followed by colorectal (11.2%), kidney (10.7%), and stomach cancers (8.9%). The standardised incidence ratio for all-site cancer was 3.9. The risks of Kaposi sarcoma (192.9) and kidney cancer (21.1) were more than 10 times those of the general population. Cancer-related deaths were 89 (14.9%) with liver cancer being the highest (14.6%), followed by lung cancer (13.5%), non-Hodgkin lymphoma (NHL) (12.4%), stomach cancer (9.0%), and colorectal cancer (7.9%). The standardised mortality ratio (SMR) was slightly elevated (1.4). A notable increase in SMR was observed for lymphoma (9.3 for Hodgkin lymphoma and 5.5 for NHL). Older age and graft failure were significantly related to PTM. These findings reflecting geographical variation have implications for the development of strategies for fatal cancers to prevent premature deaths from PTM.


Assuntos
Transplante de Rim/mortalidade , Neoplasias/epidemiologia , Adulto , Fatores Etários , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/mortalidade , Feminino , Humanos , Incidência , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/mortalidade , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/mortalidade , Linfoma não Hodgkin/epidemiologia , Linfoma não Hodgkin/mortalidade , Masculino , Pessoa de Meia-Idade , Mortalidade , Neoplasias/mortalidade , República da Coreia/epidemiologia , Estudos Retrospectivos , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/mortalidade , Neoplasias da Glândula Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/mortalidade
13.
PLoS One ; 15(7): e0236274, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32722695

RESUMO

Mortality at an early stage after kidney transplantation is a catastrophic event. Treatment-related mortality (TRM) within 1 or 3 months after kidney transplantation has been seldom reported. We designed a retrospective observational cohort study using a national population-based database, which included information about all kidney recipients between 2003 and 2016. A total of 16,073 patients who underwent kidney transplantation were included. The mortality rates 1 month (early TRM) and 3 months (TRM) after transplantation were 0.5% (n = 74) and 1.0% (n = 160), respectively. Based on a multivariate analysis, older age (hazard ratio [HR] = 1.06; P < 0.001), coronary artery disease (HR = 3.02; P = 0.002), and hemodialysis compared with pre-emptive kidney transplantation (HR = 2.53; P = 0.046) were the risk factors for early TRM. Older age (HR = 1.07; P < 0.001), coronary artery disease (HR = 2.88; P < 0.001), and hemodialysis (HR = 2.35; P = 0.004) were the common independent risk factors for TRM. In contrast, cardiac arrhythmia (HR = 1.98; P = 0.027) was associated only with early TRM, and fungal infection (HR = 2.61; P < 0.001), and epoch of transplantation (HR = 0.34; P < 0.001) were the factors associated with only TRM. The identified risk factors should be considered in patient counselling, selection, and management to prevent TRM.


Assuntos
Doença Enxerto-Hospedeiro/mortalidade , Transplante de Rim , Adulto , Fatores Etários , Idoso , Estudos de Coortes , Doença da Artéria Coronariana/complicações , Feminino , Doença Enxerto-Hospedeiro/etiologia , Humanos , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Diálise Renal , Fatores de Risco , Taxa de Sobrevida , Transplante Homólogo
15.
Nat Commun ; 11(1): 2127, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32358544

RESUMO

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular events in humans with type 2 diabetes (T2D); however, the underlying mechanism remains unclear. Activation of the NLR family, pyrin domain-containing 3 (NLRP3) inflammasome and subsequent interleukin (IL)-1ß release induces atherosclerosis and heart failure. Here we show the effect of SGLT2 inhibitor empagliflozin on NLRP3 inflammasome activity. Patients with T2D and high cardiovascular risk receive SGLT2 inhibitor or sulfonylurea for 30 days, with NLRP3 inflammasome activation analyzed in macrophages. While the SGLT2 inhibitor's glucose-lowering capacity is similar to sulfonylurea, it shows a greater reduction in IL-1ß secretion compared to sulfonylurea accompanied by increased serum ß-hydroxybutyrate (BHB) and decreased serum insulin. Ex vivo experiments with macrophages verify the inhibitory effects of high BHB and low insulin levels on NLRP3 inflammasome activation. In conclusion, SGLT2 inhibitor attenuates NLRP3 inflammasome activation, which might help to explain its cardioprotective effects.


Assuntos
Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Idoso , Animais , Doenças Cardiovasculares/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Glucose/farmacologia , Humanos , Insulina/metabolismo , Interleucina-1beta/metabolismo , Cetonas/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Pessoa de Meia-Idade , Inibidores do Transportador 2 de Sódio-Glicose , Compostos de Sulfonilureia/farmacologia , Fator de Necrose Tumoral alfa/metabolismo
16.
BMC Cancer ; 20(1): 185, 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32131779

RESUMO

BACKGROUND: To analyze the effects of BRCA1/2 mutations on chemotherapy response scores (CRS) and survival in a cohort of patients with advanced-stage ovarian cancer who were treated with neoadjuvant chemotherapy (NAC) followed by interval debulking surgery (IDS). METHODS: We retrospectively reviewed the medical records of 169 high-grade serous ovarian cancer patients who underwent a germline BRCA1/2 test and received three cycles of NAC at the Yonsei Cancer Center from 2006 to 2018. Chemotherapy response scores were compared in patients with and without BRCA1/2 mutations. The effects of BRCA1/2 mutations and CRS on survival were evaluated. RESULTS: BRCA1/2 mutations were detected in 47 (28.1%) of the 169 patients. Overall, 16 (34.0%) patients with BRCA1/2 mutations had a CRS 3 to chemotherapy compared to scores of 43 in patients (35.2%) without a mutation. Response scores of 3 in patients with BRCA1/2 mutations were not significantly associated with either improved progression-free survival (PFS) (P = 0.949) or overall survival (OS) (P = 0.168). However, CRS 3 in patients without BRCA mutations was significantly associated with both improved PFS (P = 0.030) and OS (P = 0.039). In patients with CRS1/2, carriers of BRCA1/2 mutations had better PFS (P = 0.0344) and OS (P = 0.043) than wild-type BRCA genotype patients. CONCLUSION: In ovarian cancer patients treated with NAC, CRS did not predict survival for BRCA 1/2 mutation carriers but did for BRCA wild-type patients.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Cistadenocarcinoma Seroso/terapia , Tratamento Farmacológico/métodos , Mutação em Linhagem Germinativa , Procedimentos Cirúrgicos em Ginecologia/métodos , Neoplasias Ovarianas/terapia , Adulto , Idoso , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Procedimentos Cirúrgicos de Citorredução , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento
17.
Biomolecules ; 10(3)2020 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-32183147

RESUMO

ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) are a family of multidomain extracellular protease enzymes with 19 members. A growing number of ADAMTS family gene variants have been identified in patients with various hereditary diseases. To understand the genomic landscape and mutational spectrum of ADAMTS family genes, we evaluated all reported variants in the ClinVar database and Human Gene Mutation Database (HGMD), as well as recent literature on Mendelian hereditary disorders associated with ADAMTS family genes. Among 1089 variants in 14 genes reported in public databases, 307 variants previously suggested for pathogenicity in Mendelian diseases were comprehensively re-evaluated using the American College of Medical Genetics and Genomics (ACMG) 2015 guideline. A total of eight autosomal recessive genes were annotated as being strongly associated with specific Mendelian diseases, including two recently discovered genes (ADAMTS9 and ADAMTS19) for their causality in congenital diseases (nephronophthisis-related ciliopathy and nonsyndromic heart valve disease, respectively). Clinical symptoms and affected organs were extremely heterogeneous among hereditary diseases caused by ADAMTS family genes, indicating phenotypic heterogeneity despite their structural and functional similarity. ADAMTS6 was suggested as presenting undiscovered pathogenic mutations responsible for novel Mendelian disorders. Our study is the first to highlight the genomic landscape of ADAMTS family genes, providing an appropriate genetic approach for clinical use.


Assuntos
Proteínas ADAMTS , Proteína ADAMTS9 , Ciliopatias , Bases de Dados de Ácidos Nucleicos , Cardiopatias Congênitas , Mutação , Proteínas ADAMTS/genética , Proteínas ADAMTS/metabolismo , Proteína ADAMTS9/genética , Proteína ADAMTS9/metabolismo , Ciliopatias/genética , Ciliopatias/metabolismo , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/metabolismo , Humanos
18.
Ear Hear ; 41(1): 114-124, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31045651

RESUMO

OBJECTIVES: Late-onset, down-sloping sensorineural hearing loss has many genetic and nongenetic etiologies, but the proportion of this commonly encountered type of hearing loss attributable to genetic causes is not well known. In this study, the authors performed genetic analysis using next-generation sequencing techniques in patients showing late-onset, down-sloping sensorineural hearing loss with preserved low-frequency hearing, and investigated the clinical implications of the variants identified. DESIGN: From a cohort of patients with hearing loss at a tertiary referral hospital, 18 unrelated probands with down-sloping sensorineural hearing loss of late onset were included in this study. Down-sloping hearing loss was defined as a mean low-frequency threshold at 250 Hz and 500 Hz less than or equal to 40 dB HL and a mean high-frequency threshold at 1, 2, and 4 kHz greater than 40 dB HL. The authors performed whole-exome sequencing and segregation analysis to identify the genetic causes and evaluated the outcomes of auditory rehabilitation in the patients. RESULTS: There were nine simplex and nine multiplex families included, in which the causative variants were found in six of 18 probands, demonstrating a detection rate of 33.3%. Various types of variants, including five novel and three known variants, were detected in the MYH14, MYH9, USH2A, COL11A2, and TMPRSS3 genes. The outcome of cochlear and middle ear implants in patients identified with pathogenic variants was satisfactory. There was no statistically significant difference between pathogenic variant-positive and pathogenic variant-negative groups in terms of onset age, family history of hearing loss, pure-tone threshold, or speech discrimination scores. CONCLUSIONS: The proportion of patients with late-onset, down-sloping hearing loss identified with potentially causative variants was unexpectedly high. Identification of the causative variants will offer insights on hearing loss progression and prognosis regarding various modes of auditory rehabilitation, as well as possible concomitant syndromic features.


Assuntos
Surdez , Auxiliares de Audição , Perda Auditiva Neurossensorial , Perda Auditiva , Audiometria de Tons Puros , Limiar Auditivo , Audição , Perda Auditiva Neurossensorial/genética , Humanos , Proteínas de Membrana , Proteínas de Neoplasias , Serina Endopeptidases
19.
Exp Mol Med ; 51(8): 1-12, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31434872

RESUMO

KCNQ4 is frequently mutated in autosomal dominant non-syndromic hearing loss (NSHL), a typically late-onset, initially high-frequency loss that progresses over time (DFNA2). Most KCNQ4 mutations linked to hearing loss are clustered around the pore region of the protein and lead to loss of KCNQ4-mediated potassium currents. To understand the contribution of KCNQ4 variants to NSHL, we surveyed public databases and found 17 loss-of-function and six missense KCNQ4 variants affecting amino acids around the pore region. The missense variants have not been reported as pathogenic and are present at a low frequency (minor allele frequency < 0.0005) in the population. We examined the functional impact of these variants, which, interestingly, induced a reduction in potassium channel activity without altering expression or trafficking of the channel protein, being functionally similar to DFNA2-associated KCNQ4 mutations. Therefore, these variants may be risk factors for late-onset hearing loss, and individuals harboring any one of these variants may develop hearing loss during adulthood. Reduced channel activity could be rescued by KCNQ activators, suggesting the possibility of medical intervention. These findings indicate that KCNQ4 variants may contribute more to late-onset NSHL than expected, and therefore, genetic screening for this gene is important for the prevention and treatment of NSHL.


Assuntos
Bases de Dados Genéticas , Perda Auditiva/genética , Ativação do Canal Iônico/genética , Canais de Potássio KCNQ/genética , Mutação , Animais , Células CHO , Cricetinae , Cricetulus , Surdez/genética , Surdez/fisiopatologia , Frequência do Gene , Células HEK293 , Audição/genética , Perda Auditiva/fisiopatologia , Humanos , Ativação do Canal Iônico/fisiologia , Setor Público
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