Characterization of Vestibular Phenotypes in Patients with Genetic Hearing Loss.

Background: The vestibular phenotypes of patients with genetic hearing loss are poorly understood. Methods: we performed genetic testing including exome sequencing and vestibular function tests to investigate vestibular phenotypes and functions in patients with genetic hearing loss. Results: Among 627 patients, 143 (22.8%) had vestibular symptoms. Genetic variations were confirmed in 45 (31.5%) of the 143 patients. Nineteen deafness genes were linked with vestibular symptoms; the most frequent genes in autosomal dominant and recessive individuals were COCH and SLC26A4, respectively. Vestibular symptoms were mostly of the vertigo type, recurrent, and persisted for hours in the genetically confirmed and unconfirmed groups. Decreased vestibular function in the caloric test, video head impulse test, cervical vestibular-evoked myogenic potential, and ocular vestibular-evoked myogenic potential was observed in 42.0%, 16.3%, 57.8%, and 85.0% of the patients, respectively. The caloric test revealed a significantly higher incidence of abnormal results in autosomal recessive individuals than in autosomal dominant individuals (p = 0.011). The genes, including SLC26A4, COCH, KCNQ4, MYH9, NLRP3, EYA4, MYO7A, MYO15A, and MYH9, were heterogeneously associated with abnormalities in the vestibular function test. Conclusions: In conclusion, diverse vestibular symptoms are commonly concomitant with genetic hearing loss and are easily overlooked.

Prevalence and Clinical Characteristics of Mitochondrial DNA Mutations in Korean Patients With Sensorineural Hearing Loss.

BACKGROUND: Mutations in mitochondrial DNA (mtDNA) are associated with several genetic disorders, including sensorineural hearing loss. However, the prevalence of mtDNA mutations in a large cohort of Korean patients with hearing loss has not yet been investigated. Thus, this study aimed to investigate the frequency of mtDNA mutations in a cohort of with pre- or post-lingual hearing loss of varying severity. METHODS: A total of 711 Korean families involving 1,099 individuals were evaluated. Six mitochondrial variants associated with deafness (MTRNR1 m.1555A>G, MTTL1 m.3243A>G, MTCO1 m.7444G>A and m.7445A>G, and MTTS1 m.7471dupC and m.7511T>C) were screened using restriction fragment length polymorphism. The prevalence of the six variants was also analyzed in a large control dataset using whole-genome sequencing data from 4,534 Korean individuals with unknown hearing phenotype. RESULTS: Overall, 12 of the 711 (1.7%) patients with hearing loss had mtDNA variants, with 10 patients from independent families positive for the MTRNR1 m.1555A>G mutation and 2 patients positive for the MTCO1 m.7444G>A mutation. The clinical characteristics of patients with the mtDNA variants were characterized by post-lingual progressive hearing loss due to the m.1555A>G variant (9 of 472; 1.9%). In addition, 18/4,534 (0.4%) of the Korean population have mitochondrial variants associated with hearing loss, predominantly the m.1555A>G variant. CONCLUSION: A significant proportion of Korean patients with hearing loss is affected by the mtDNA variants, with the m.1555A>G variant being the most prevalent. These results clarify the genetic basis of hearing loss in the Korean population and emphasize the need for genetic testing for mtDNA variants.

Novel Variant in CEP250 Causes Protein Mislocalization and Leads to Nonsyndromic Autosomal Recessive Type of Progressive Hearing Loss.

Genetic hearing loss is the most common hereditary sensorial disorder. Though more than 120 genes associated with deafness have been identified, unveiled causative genes and variants of diverse types of hearing loss remain. Herein, we identified a novel nonsense homozygous variant in CEP250 (c.3511C>T; p.Gln1171Ter) among the family members with progressive moderate sensorineural hearing loss in nonsyndromic autosomal recessive type but without retinal degeneration. CEP250 encodes C-Nap1 protein belonging to the CEP protein family, comprising 30 proteins that play roles in centrosome aggregation and cell cycle progression. The nonsense variant in CEP250 led to the early truncating protein of C-Nap1, which hindered centrosome localization; heterologous expression of CEP250 (c.3511C>T) in NIH3T3 cells within cilia expression condition revealed that the truncating C-Nap1 (p.Gln1171Ter) was not localized at the centrosome but was dispersed in the cytosol. In the murine adult cochlea, Cep250 was expressed in the inner and outer hair cells. Knockout mice of Cep250 showed significant hair cell degeneration and progressive hearing loss in auditory brainstem response. In conclusion, a nonsense variant in CEP250 results in a deficit of centrosome localization and hair cell degeneration in the cochlea, which is associated with the progression of hearing loss in humans and mice.

Overlooked KCNQ4 variants augment the risk of hearing loss.

Pathogenic variants of KCNQ4 cause symmetrical, late-onset, progressive, high-frequency-affected hearing loss, which eventually involves all frequencies with age. To understand the contribution of KCNQ4 variants to hearing loss, we analyzed whole-exome and genome sequencing data from patients with hearing loss and individuals whose hearing phenotypes were unknown. In KCNQ4, we identified seven missense variants and one deletion variant in 9 hearing loss patients and 14 missense variants in the Korean population with an unknown hearing loss phenotype. The p.R420W and p.R447W variants were found in both cohorts. To investigate the effects of these variants on KCNQ4 function, we performed whole-cell patch clamping and examined their expression levels. Except for p.G435Afs*61, all KCNQ4 variants exhibited normal expression patterns similar to those of wild-type KCNQ4. The p.R331Q, p.R331W, p.G435Afs*61, and p.S691G variants, which were identified in patients with hearing loss, showed a potassium (K+) current density lower than or similar to that of p.L47P, a previously reported pathogenic variant. The p.S185W and p.R216H variants shifted the activation voltage to hyperpolarized voltages. The channel activity of the p.S185W, p.R216H, p.V672M, and p.S691G KCNQ4 proteins was rescued by the KCNQ activators retigabine or zinc pyrithione, whereas p.G435Afs*61 KCNQ4 proteins were partially rescued by sodium butyrate, a chemical chaperone. Additionally, the structure of the variants predicted using AlphaFold2 showed impaired pore configurations, as did the patch-clamp data. Our findings suggest that KCNQ4 variants may be overlooked in hearing loss that starts in adulthood. Some of these variants are medically treatable; hence, genetic screening for KCNQ4 is important.

Comprehensive Prediction Model, Including Genetic Testing, for the Outcomes of Cochlear Implantation.

OBJECTIVES: Despite growing interest in the genetic contribution to cochlear implant (CI) outcomes, only a few studies with limited samples have examined the association of CI outcomes with genetic etiologies. We analyzed CI outcomes using known predictors and genetic testing results to obtain a comprehensive understanding of the impact of genetic etiologies. DESIGN: We retrospectively reviewed the medical records and images of patients who underwent cochlear implantation and genetic testing at a single tertiary medical institution, between May 2008 and December 2020. After excluding those whose speech test results were unavailable, and those in whom the implant was removed due to complications, such as infection or device failure, 203 patients were included in this study. The participants were categorized into adult (≥19 years), child (2-18 years), and infant (<24 months) groups. Outcomes were measured based on categories of auditory perception, monosyllable, disyllable, and sentence scores. For the infant group, the Infant-Toddler Meaningful Auditory Integration Scale score was used. RESULTS: Among the 203 participants, a causative genetic variant was identified in 117 (57.6%) individuals. The presence of a causative variant was significantly associated with better CI outcomes in the infant group (ß = 0.23; 95% confidence interval, 0.01 to 0.47; p = 0.044), but not in the child and adult groups. In the genetically confirmed patients without cochlear malformation, genetic variants involving the spiral ganglion was a poor prognostic factor in the child group (ß = -57.24; 95% confidence interval, -90.63 to -23.75; p = 0.004). CONCLUSIONS: The presence of known genetic etiology of hearing loss was associated with better CI outcomes in the infant group, but not in the child and adult groups. A neural-type genetic variant was a poor prognostic factor in the genetically diagnosed child subgroup without cochlear malformation. Careful genetic counseling should be performed before cochlear implantation.

Prevalence of Vitamin D Deficiency in Children with Fractures: Before and during the COVID-19 Outbreak.

Background: Although it is generally agreed that vitamin D is important for bone health, the role of vitamin D in preventing fractures in children and adolescents remains unclear. Therefore, this study aimed to investigate the prevalence of vitamin D deficiency and insufficiency in healthy Korean children with fractures. Our secondary aim was to compare serum vitamin D levels before and during the coronavirus disease 2019 (COVID-19) outbreak. Methods: We evaluated 334 patients with fractures who were surgically treated at our institution between 2018 and 2019 before the onset of COVID-19 (group I). In addition, we collected data on the serum 25(OH)D levels of 210 patients who visited our pediatric department for evaluation of short stature (group II) and the serum 25(OH)D levels of the patients with fractures during the COVID-19 pandemic period (group III). A serum 25(OH)D level of <20 ng/mL was considered deficient, between 20 and 32 ng/mL was insufficient, and ≥32 ng/mL was considered sufficient. Results: The mean age was 8.1 ± 3.5 years in group I, 8.2 ± 3.7 years in group II, and 8.6 ± 3.5 years in group III. The prevalence of vitamin D deficiency was 53.0% in group I and 32.9% in group II. The mean serum 25(OH)D level was lower in group I than in group II (20.0 ± 7.3 ng/ml vs. 23.2 ± 6.9 ng/ml, p < 0.001). The mean serum 25(OH)D level of younger patients (<10 years) in group III was lower than that of the younger patients in the prepandemic period (21.4 ± 7.2 ng/mL vs. 19.2 ± 6.8 ng/mL, p=0.037). Conclusions: We observed a high prevalence of vitamin D deficiency/insufficiency in children with fractures who required surgical treatment. During the COVID-19 pandemic, the serum vitamin D levels became even lower, especially in younger children.

Medial Epicondyle Fracture in Children and Its Association with Increased Carrying Angle.

Background: This study aimed to evaluate the injury mechanism of medial epicondylar fractures in children and adolescents and its association with increased carrying angle (CA) as a predisposing factor. Materials and Methods: We evaluated 37 patients with medial epicondylar fractures who were surgically treated at our institution. Medical records and plain radiographs were reviewed to determine the mechanism of injury and the humerus-elbow-wrist angle (HEWA) and CA of the uninjured arm. To evaluate the effect of coronal alignment on specific fracture type, we compared the CA and HEWA of the 23 patients with medial epicondylar fracture who were injured by falling onto an outstretched hand (group I) with age- and sex-matched controls of 23 patients who had sustained extension-type supracondylar fractures (group II). Results: The mean age at injury was 11.7 ± 2.8 years (range, 5 to 16 years). Of the 37 patients, 23 (62.2%) recalled the injury mechanism as falling onto an outstretched hand and 10 patients (27.0%) were injured while arm wrestling, and in one patient (2.7%), the injury was associated with elbow dislocation. In the case-matched analysis, the mean HEWA of group I was 13.1 ± 2.8° (range, 7.1° to 19.8°) and the mean CA was 17.7 ± 2.7° (range, 13.0° to 22.2°). These angles were significantly increased in group I (p=0.003 and p=0.001, respectively). Conclusion: Falling onto an outstretched hand is the most common injury mechanism in patients with medial epicondylar fractures, and these fractures are associated with an increased CA.

Clinical Heterogeneity Associated with MYO7A Variants Relies on Affected Domains.

Autosomal dominant hearing loss (ADHL) manifests as an adult-onset disease or a progressive disease. MYO7A variants are associated with DFNA11, a subtype of ADHL. Here, we examined the role and genotype-phenotype correlation of MYO7A in ADHL. Enrolled families suspected of having post-lingual sensorineural hearing loss were selected for exome sequencing. Mutational alleles in MYO7A were identified according to ACMG guidelines. Segregation analysis was performed to examine whether pathogenic variants segregated with affected status of families. All identified pathogenic variants were evaluated for a phenotype-genotype correlation. MYO7A variants were detected in 4.7% of post-lingual families, and 12 of 14 families were multiplex. Five potentially pathogenic missense variants were identified. Fourteen variants causing autosomal dominant deafness were clustered in motor and MyTH4 domains of MYO7A protein. Missense variants in the motor domain caused late onset of hearing loss with ascending tendency. A severe audiological phenotype was apparent in individuals carrying tail domain variants. We report two new pathogenic variants responsible for DFNA11 in the Korean ADHL population. Dominant pathogenic variants of MYO7A occur frequently in motor and MyTH4 domains. Audiological differences among individuals correspond to specific domains which contain the variants. Therefore, appropriate rehabilitation is needed, particularly for patients with late-onset familial hearing loss.

OSBPL2 mutations impair autophagy and lead to hearing loss, potentially remedied by rapamycin.

Intracellular accumulation of mutant proteins causes proteinopathies, which lack targeted therapies. Autosomal dominant hearing loss (DFNA67) is caused by frameshift mutations in OSBPL2. Here, we show that DFNA67 is a toxic proteinopathy. Mutant OSBPL2 accumulated intracellularly and bound to macroautophagy/autophagy proteins. Consequently, its accumulation led to defective endolysosomal homeostasis and impaired autophagy. Transgenic mice expressing mutant OSBPL2 exhibited hearing loss, but osbpl2 knockout mice or transgenic mice expressing wild-type OSBPL2 did not. Rapamycin decreased the accumulation of mutant OSBPL2 and partially rescued hearing loss in mice. Rapamycin also partially improved hearing loss and tinnitus in individuals with DFNA67. Our findings indicate that dysfunctional autophagy is caused by mutant proteins in DFNA67; hence, we recommend rapamycin for DFNA67 treatment.Abbreviations: ABR: auditory brainstem response; ACTB: actin beta; CTSD: cathepsin D; dB: decibel; DFNA67: deafness non-syndromic autosomal dominant 67; DPOAE: distortion product otoacoustic emission; fs: frameshift; GFP: green fluorescent protein; HsQ53R-TG: human p.Q53Rfs*100-transgenic: HEK 293: human embryonic kidney 293; HFD: high-fat diet; KO: knockout; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; NSHL: non-syndromic hearing loss; OHC: outer hair cells; OSBPL2: oxysterol binding protein-like 2; SEM: scanning electron microscopy; SGN: spiral ganglion neuron; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; TG: transgenic; WES: whole-exome sequencing; YUHL: Yonsei University Hearing Loss; WT: wild-type.

Differential genetic diagnoses of adult post-lingual hearing loss according to the audiogram pattern and novel candidate gene evaluation.

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.

COCH-related autosomal dominant nonsyndromic hearing loss: a phenotype-genotype study.

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.

Trampoline-related fractures of the proximal tibia in children.

BACKGROUND: Trampoline-related fractures of the proximal tibial metaphysis are common in children and have been linked to subsequent valgus deformity of the tibia. The purpose of this study was to investigate the characteristics of trampoline-related proximal tibial fractures in young children. METHODS: We evaluated 40 patients with proximal tibial fracture after trampolining between 2013 and 2019. The median duration of follow-up was 18 months. Standing long leg radiographs were obtained at the last follow-up to evaluate angular deformity and limb length inequality in the patients. The measurements recorded include the lower limb length, mechanical lateral distal femoral angle (mLDFA), medial proximal tibial angle (MPTA), mechanical axis deviation (MAD), and anatomical tibio-femoral angle (aTFA). The anterior tilt angle (ATA) was measured using a lateral radiograph of the tibia. RESULTS: The median age at injury was 40.0 months. Using trampoline with a heavier person was the most common mechanism of injury. aTFA and MAD were found to be increased towards the valgus at the last follow-up in our patient; however, the increase was not statistically significant (p = 0.692 and p = 0.973, respectively). The anterior tilt angle was increased in the injured leg at the last follow-up. But the change was not statistically significant (p = 0.09). CONCLUSIONS: Using trampoline with a heavier person carries the risk of trampoline-related proximal tibial fracture in young children. We did not find a significant change in limb alignment at a minimum of one year of follow-up.

Feasibility and Effectiveness of a Motion Tracking-Based Online Fitness Program for Office Workers.

The development of technology-based home fitness has emerged from the booming digital healthcare market and recent demands for at-home fitness and health equipment due to the COVID-19 pandemic. Digital healthcare company Alyce Healthcare recently developed Weelo, which is a web-based online fitness program. Weelo recommends an exercise protocol through machine-learning-enabled recognition of the user's motion and provides visual and auditory feedback. We evaluated whether Weelo improves physical and mental well-being to assess its capabilities and effectiveness. Thirty-two participants performed a total of 20 exercise sessions following the Weelo guide on a laptop. The participants were evaluated using a before and after exercise program, body composition, handgrip strength, six-minute walk test, modified star excursion balance test, short form 36, fatigue severity scale, Beck depression index, and a satisfaction survey. Overall, there was a significant improvement in muscle strength, endurance, and balance ability, as well as an improved quality of life and significant reduction in fatigue and depression. Participants showed high motivation to continue following the Weelo exercise program. In conclusion, utilizing Weelo improved physical and mental well-being and is considered to be an individual-use indoor exercise program that serves as an alternative to traditional face-to-face exercise.

Heterogeneity of MYO15A variants significantly determine the feasibility of acoustic stimulation with hearing aid and cochlear implant.

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.

Low vitamin D levels in post-menopausal women are associated with complex regional pain syndrome type I in surgically treated distal radius fractures.

BACKGROUND: Complex regional pain syndrome type I (CRPS I) is a chronic devastating condition and a relatively common complication of distal radius fractures (DRF). The purpose of this study was to investigate the relationship of vitamin D levels in surgically treated post-menopausal women with CRPS I occurrence in DRF. METHODS: From February 2016 to March 2017, 158 surgically treated post-menopausal patients with DRF were enrolled. Exclusion criteria were (1) patients who had been taking vitamin D or osteoporosis medication at the time of injury; (2) patients with medical factors that may affect vitamin D levels; (3) patients who were reluctant to enroll in the study; and (4) patient with additional fractures, ligamentous injuries, or neuropathy. A total of 107 patients were available for final analysis. We compared the serum vitamin D levels in post-menopausal women with DRF with CRPS I (group 1) and without CRPS I (group 2). Bone mineral density (BMD) of the femur and spine, osteocalcin, alkaline phosphatase (ALP), body mass index (BMI) were also measured. RESULTS: The average age at the time of surgery was 66.5 years (range, 39-86 years). The mean follow-up period was 16.3 months after surgery. Among the 107 surgically treated DRF patients, 19 (18%) met the Budapest criteria for CRPS I during the follow-up period. The mean serum vitamin D level in group 1 (15.2 ng/ml) was significantly lower than that in group 2 (20.5 ng/ml, p = 0.027). The mean values of osteocalcin, ALP, BMI, and BMD were not significantly different between the groups. CONCLUSION: Lower vitamin D levels in post-menopausal women can increase CRPS I occurrence in distal radius fractures.

Architecture of the Triceps Surae Muscles Complex in Patients with Spastic Hemiplegia: Implication for the Limited Utility of the Silfverskiöld Test.

The Silfverskiöld test has long been used as an important tool for determining the affected muscles of the triceps surae in patients with equinus deformity. However, the test may not reflect the altered interactions between the muscles of the triceps which are affected by spasticity. The purpose of this study was to compare the architectural properties of the triceps surae muscles complex using ultrasonography, between hemiplegic patients and typically-developing children. Specifically, we wished to examine any differences in the architecture of the three muscles with various angle configurations of the knee and ankle joints. Ultrasound images of the medial gastrocnemius, lateral gastrocnemius, and soleus were acquired from paretic (group I) and non-paretic (group II) legs of ten patients and the legs (group III) of 10 age-matched normal children. A mixed model was used to evaluate the differences in the measurements of muscle architecture among the groups and the effects of various joint configurations on the measurements within the muscles. Compared to the results of measurements in groups II and III, the fascicle length was not different in the medial gastrocnemius of a paretic leg but it was longer in the lateral gastrocnemius and shorter in the soleus; the pennation angle was smaller in both medial and lateral gastrocnemii and was not different in the soleus; and the muscle thickness was found to be reduced in the three muscles of the paretic leg. Contrary to the observations in both the medial and lateral gastrocnemii, the fascicle length was increased and the pennation angle was decreased in the soleus with an increase of knee flexion. Through the current simulation study of the Silfverskiöld test using ultrasonography, we found that the changes detected in the architectural properties of the three muscles induced by systematic variations of the position at the ankle and the knee joints were variable. We believe that the limited utility of the Silfverskiöld test should be considered in determining an appropriate operative procedure to correct the equinus deformity in patients with altered architecture of the muscles in conditions such as cerebral palsy, as the differing muscle architectures of the triceps surae complex may affect the behavior of the muscles during the Silfverskiöld test.

Concurrent Index-to-Little Finger Dorsal Dislocations of the Carpometacarpal Joints with Carpal Bone Fractures.

A 32-year-old man presented with simultaneous dorsal dislocations of the index-to-little finger carpometacarpal (CMC) joint with carpal bone fractures. Closed reduction was unsuccessful even after general anesthesia. During open dorsal approach, we found interposed joint capsule in the CMC joints and after removal of the joint capsule open reduction was easily achieved. We placed four Kirschner wires through the CMC joint. Furthermore, the fractured dorsal fragments of the trapezoid and hamate were fixed with mini screw in each. During 1-year followup, the patient showed good recovery and no evidence of posttraumatic arthritic changes in plain X-ray. We recommend to fix the dorsal fragment of the carpal bone with screws as well as the transarticular fixation of the CMC joint in case of concurrent CMC joint fracture-dislocation of all four fingers.

A recurrent mutation in KCNQ4 in Korean families with nonsyndromic hearing loss and rescue of the channel activity by KCNQ activators.

Mutations in potassium voltage-gated channel subfamily Q member 4 (KCNQ4) are etiologically linked to nonsyndromic hearing loss (NSHL), deafness nonsyndromic autosomal dominant 2 (DFNA2). To identify causative mutations of hearing loss in 98 Korean families, we performed whole exome sequencing. In four independent families with NSHL, we identified a cosegregating heterozygous missense mutation, c.140T>C (p.Leu47Pro), in KCNQ4. Individuals with the c.140T>C KCNQ4 mutation shared a haplotype flanking the mutated nucleotide, suggesting that this mutation may have arisen from a common ancestor in Korea. The mutant KCNQ4 protein could reach the plasma membrane and interact with wild-type (WT) KCNQ4, excluding a trafficking defect; however, it exhibited significantly decreased voltage-gated potassium channel activity and fast deactivation kinetics compared with WT KCNQ4. In addition, when co-expressed with WT KCNQ4, mutant KCNQ4 protein exerted a dominant-negative effect. Interestingly, the channel activity of the p.Leu47Pro KCNQ4 protein was rescued by the KCNQ activators MaxiPost and zinc pyrithione. The c.140T>C (p.Leu47Pro) mutation in KCNQ4 causes progressive NSHL; however, the defective channel activity of the mutant protein can be rescued using channel activators. Hence, in individuals with the c.140T>C mutation, NSHL is potentially treatable, or its progression may be delayed by KCNQ activators.

Whole-exome sequencing identifies two novel mutations in KCNQ4 in individuals with nonsyndromic hearing loss.

Mutations in potassium voltage-gated channel subfamily Q member 4 (KCNQ4) are etiologically linked to a type of nonsyndromic hearing loss, deafness nonsyndromic autosomal dominant 2 (DFNA2). We performed whole-exome sequencing for 98 families with hearing loss and found mutations in KCNQ4 in five families. In this study, we characterized two novel mutations in KCNQ4: a missense mutation (c.796G>T; p.Asp266Tyr) and an in-frame deletion mutation (c.259_267del; p.Val87_Asn89del). p.Asp266Tyr located in the channel pore region resulted in early onset and moderate hearing loss, whereas p.Val87_Asn89del located in the N-terminal cytoplasmic region resulted in late onset and high frequency-specific hearing loss. When heterologously expressed in HEK 293 T cells, both mutant proteins did not show defects in protein trafficking to the plasma membrane or in interactions with wild-type (WT) KCNQ4 channels. Patch-clamp analysis demonstrated that both p.Asp266Tyr and p.Val87_Asn89del mutant channels lost conductance and were completely unresponsive to KCNQ activators, such as retigabine, zinc pyrithione, and ML213. Channels assembled from WT-p.Asp266Tyr concatemers, like those from WT-WT concatemers, exhibited conductance and responsiveness to KCNQ activators. However, channels assembled from WT-p.Val87_Asn89del concatemers showed impaired conductance, suggesting that p.Val87_Asn89del caused complete loss-of-function with a strong dominant-negative effect on functional WT channels. Therefore, the main pathological mechanism may be related to loss of K+ channel activity, not defects in trafficking.