Journal of Bio-X Research
Volume 04 · Issue 04 · 2021
J Bio-X Res
- Sections
- Review Article
- Research Article
Preimplantation genetic diagnosis (PGD) uses molecular biological techniques to genetically diagnose embryos before in vitro fertilization. The information obtained through PGD can help clinicians select healthy embryos for implantation, prevent the transmission of inherited diseases and help affected families have healthy children. This paper reviews the development of PGD technology, the history of its application to hereditary hearing loss, and the general process of how PGD is applied to screen for hereditary hearing loss. The aim of this review is to demonstrate the reliability of PGD in the primary prevention of hereditary hearing loss, assist clinicians in counseling patients at risk of transmitting an inherited disease, and explore the journey from PGD to in vitro fertilization. Given that the application of PGD technology to hereditary hearing loss varies in different countries and regions, there is still a long way to go before PGD is routinely applied for the primary prevention of hereditary hearing loss.
Sensorineural hearing loss is the most common sensory deficit in humans, with an estimated prevalence of 1 in 500 newborns. Approximately half of childhood hearing loss is attributed to genetic factors and can be classified as syndromic or non-syndromic based on the inheritance pattern. The ion channel genes KCNQ1, KCNE1, KCNQ4, P2RX2, TMC1, KCNJ10, and CACNA1D have frequently been associated with genetic hearing loss. Because of the important roles these genes play in cochlear hair cell function and the auditory pathways, mutations in these genes that result in impaired ion channel function can lead to hereditary hearing loss. The main purpose of this review was to examine the latest research progress on the functional roles, inheritance pattern, gene expression, protein structure, clinical phenotypes, mouse models, and possible treatments of the most commonly studied ion channels associated with inherited deafness. A comprehensive summary could help highlight ion channels that should be investigated as potential drug targets for the treatment of inherited deafness.
KCNQ4 gene mutation can lead to deafness non-syndromic autosomal dominant 2A, which is a type of autosomal dominant non-syndromic hearing loss. Deafness non-syndromic autosomal dominant 2A patients with KCNQ4 gene mutation usually present with symmetrical, delayed, progressive high-frequency-affected hearing loss, which eventually can involve all frequencies. In this article, we comprehensively reviewed the research on the role and function of KCNQ4 gene in genetic hearing loss. We discussed the pathological and physiological mechanisms of KCNQ4 gene and the related clinical phenotypes of KCNQ4 gene mutations. We also reviewed the latest developments in the treatment of KCNQ4 gene mutation-related genetic hearing loss, including selective potassium channel activation drugs and gene therapy.
The vestibular system involves high-level sensory and cognitive processes, such as spatial perception, balance control, visual stability, and emotional control. Vestibular dysfunction can induce vertigo, blurred vision, postural imbalance, walking instability, and spatial discomfort, which causes serious damage to health. It has long been known that after peripheral vestibular lesion, vestibular dysfunction may spontaneously recover. This is known as vestibular compensation. However, at least 20% to 30% of patients with vestibular disorders cannot yield vestibular compensation and remain with vestibular dysfunction for the rest of their lives. The exploration of the biological characteristics and regulatory factors of the loss and reestablishment of vestibular function will establish a new understanding of the mechanism of vestibular compensation and provide new tools and strategies for promoting vestibular rehabilitation. We aim to comprehensively review the mechanism of vestibular compensation and discuss future directions in this field.
The zebrafish is an excellent model for studying gene function in auditory system development. Pou4f3 plays an important role in mouse hair cell formation. Here, we constructed a pou4f3-knockout Tg(Brn3c:GFP) zebrafish to provide an efficient fluorescence-visualized model for studying the molecular mechanisms of ear development.
Cas9/single guide RNAs targeting exon 2 of pou4f3 were designed and injected into one-cell stage zebrafish embryos (G0 generation). The G0 generation were crossed with Tg(Brn3c:GFP) zebrafish to obtain pou4f3-mutant Tg(Brn3c:GFP) zebrafish. The targeting efficiency was detected by polymerase chain reaction amplification and Sanger sequencing. Zebrafish hair cells were observed by laser scanning confocal microscopy in vivo. The morphology of the otoliths and semicircular canals were analyzed. All animal experiments were approved by the Animal Care and Use Committee of Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University (approval No. 2016-KY-040) on March 3, 2016.
The pou4f3-mutant Tg(Brn3c:GFP) zebrafish line was successfully established. Fluorescence observation suggested that hair cell development was delayed in pou4f3-knockout zebrafish. Knockout of pou4f3 also induced defects in the otoliths and semicircular canals and impaired ear function in zebrafish.
A CRISPR/Cas9-mediated pou4f3 mutant Tg(Brn3c:GFP) zebrafish model was established for the first time to demonstrate the essential role of pou4f3 in zebrafish ear development. Our study provides a highly efficient method for the establishment of a visualized model of gene knockout zebrafish and has the potential to allow high-throughput drug screening to explore therapeutics for related diseases.
Early identification of acute kidney injury (AKI) is essential to improve the prognosis of patients with acute heart failure (AHF). We aimed to determine the utility of neutrophil/lymphocyte ratio (NLR), N-terminal prohormone of brain natriuretic peptide (NT-proBNP), urea, and creatinine (Cr), as well as combinations of these, for the prediction of AKI in patients with AHF.
A total of 153 patients with AHF under the care of Sun Yat-sen Memorial Hospital, Sun Yat-sen University from October 2009 to October 2019 were included in this retrospective observational study. Their NLR, NT-proBNP, urea, and Cr concentrations were measured on admission. AKI was defined using the Acute Kidney Injury Network criteria. Receiver operating characteristic (ROC) curves, the areas under the curves (AUCs), sensitivity, and specificity were employed to evaluate the ability of each biomarker and their combinations to identify AKI. This study was approved by the Ethics Committee of Sun Yat-sen Memorial Hospital, Sun Yat-sen University (approval No. SYSEC-KY-KS-2021-126) on June 22, 2021.
Forty-six (30.1%) participants developed AKI during hospitalization. The NLR and NT-proBNP of the participants with AKI were higher than those without (NLR: median 7.886 vs 4.717, P < 0.0001; NT-proBNP, median 6774 vs 2786pg/mL, P < 0.0001). ROC analyses demonstrated that high NLR and NT-proBNP were associated with higher incidences of AKI (NLR: cut-off 5.681, AUC 0.716, sensitivity 58.9%, specificity 80.4%; NT-proBNP: cut-off 5320pg/mL, AUC 0.700, sensitivity 72.9%, specificity 65.2%). Moreover, a combination of NLR, NT-proBNP, urea, and Cr yielded an AUC of 0.815, sensitivity 80.4%, and specificity of 74.8%. In addition, the AUCs for the prediction of AKI in the participants with New York Heart Association (NYHA) classes II, III, and IV were 0.936, 0.860, and 0.772, respectively, using this combination.
A combination of NLR, NT-proBNP, urea, and Cr, measured at admission, may represent a promising tool for the prediction of AKI in patients with AHF. This method performs best for AKI risk assessment in patients with NYHA II, followed by those with NYHA III or IV.
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