Background: TMC1 is one of the most common deafness genes causing DFNA36. Patient-derived human induced pluripotent stem cells (iPSCs) provide an opportunity to modelling diseases. TMC1 p.M418K mutation in human is orthologous to Beethoven mice. Here, we investigated the differentiation, morphology and electrophysiological properties of hair cell-like cells (HC-like cells) derived from DFNA36 patient.
Methods: Inner ear HC-like cells were induced from iPSCs derived from DFNA36 (TMC1 p.M418K) patient (M), normal control (M) and genetic corrected iPSCs (M). Immunofluorescence, scanning electron microscopy and whole-cell patch-clamp were used to study the mechanism and influence of TMC1 p.M418K mutation.
Results: In this study we successfully generated HC-like cells from iPSCs with three different genotypes. HC-like cells from M showed defected morphology of microvilli and physiological properties compared to M. HC-like cells from M showed recovery in morphology of microvilli and physiological properties.
Conclusions: Our results indicate that TMC1 p.M418K mutation didn't influence inner ear hair cell differentiation but the morphology of microvilli and electrophysiological properties and gene correction induced recovery. CRISPR/Cas9 gene therapy is feasible in human patient with TMC1 p.M418K mutation.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10763492 | PMC |
| http://dx.doi.org/10.1186/s13287-023-03617-9 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Binding the Power of Cycloaddition and Cross-Coupling in a Single Mechanism: An Unexpected Bending Journey to Radical Chemistry of Butadiynyl with Conjugated Dienes.
J Phys Chem Lett
January 2025
Department of Chemistry, University of Hawai'i at Ma̅noa, Honolulu, Hawaii 96822, United States.
What if an experiment could combine the power of cycloaddition and cross-coupling with the formation of an aromatic molecule in a single collision? Crossed molecular beam experiments augmented with electronic structure and statistical calculations provided compelling evidence on a novel radical route involving 1,3-butadiynyl (HCCCC; X∑) radicals synthesizing (substituted) arylacetylenes in the gas phase upon reactions with 1,3-butadiene (CHCHCHCH; XA) and 2-methyl-1,3-butadiene (isoprene; CHC(CH)CHCH; XA'). This elegant mechanism merges two previously disconnected concepts of cross-coupling and cycloaddition-aromatization in a single collision event via the formation of two new C(sp)-C(sp) bonds and bending the 180° moiety of the linear 1,3-butadiynyl radical out of the ordinary by 60° to 120°. In addition to its importance to fundamental organic chemistry, this unconventional mechanism links two previously separated routes of gas-phase molecular mass growth processes of polyacetylenes and polycyclic aromatic hydrocarbons (PAHs), respectively, in low-temperature environments such as in cold molecular clouds like the Taurus Molecular Cloud (TMC-1) and in hydrocarbon-rich atmospheres of planets and their moons such as Titan, which revises the established understanding of low-temperature molecular mass growth processes in the Universe.
View Article and Find Full Text PDFComplexes of vertebrate TMC1/2 and CIB2/3 proteins form hair-cell mechanotransduction cation channels.
Elife
January 2025
Department of Otorhinolaryngology - Head & Neck Surgery, University of Maryland School of Medicine, Baltimore, United States.
Calcium and integrin-binding protein 2 (CIB2) and CIB3 bind to transmembrane channel-like 1 (TMC1) and TMC2, the pore-forming subunits of the inner-ear mechano-electrical transduction (MET) apparatus. These interactions have been proposed to be functionally relevant across mechanosensory organs and vertebrate species. Here, we show that both CIB2 and CIB3 can form heteromeric complexes with TMC1 and TMC2 and are integral for MET function in mouse cochlea and vestibular end organs as well as in zebrafish inner ear and lateral line.
View Article and Find Full Text PDFHeterogeneous Group of Genetically Determined Auditory Neuropathy Spectrum Disorders.
Int J Mol Sci
November 2024
The Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, 117513 Moscow, Russia.
Auditory neuropathy spectrum disorder (ANSD) is often missed by standard hearing tests, accounting for up to 10% of hearing impairments (HI) and commonly linked to variants in 23 genes. We assessed 122 children with HI, including 102 with sensorineural hearing loss (SNHL) and 20 with ANSD. SNHL patients were genotyped for common variants using qPCR, while ANSD patients underwent whole exome sequencing, with variants analyzed across 249 genes.
View Article and Find Full Text PDFHuman TMC1 and TMC2 are mechanically gated ion channels.
Neuron
December 2024
Institute of Molecular Physiology, Shenzhen Bay Laboratory, Shenzhen, China; Department of Neurobiology, School of Basic Medicine, Capital Medical University, Beijing, China; Institute for Medical Physiology, Chinese Institutes for Medical Research, Beijing, China. Electronic address:
Mammalian transmembrane channel-like proteins 1 and 2 (TMC1 and TMC2) have emerged as very promising candidate mechanotransduction channels in hair cells. However, controversy persists because the heterogeneously expressed TMC1/2 in cultured cells lack evidence of mechanical gating, primarily due to their absence from the plasma membrane. By employing domain swapping with OSCA1.
View Article and Find Full Text PDFWhole-exome sequencing reveals known and candidate genes for hearing impairment in Mali.
HGG Adv
January 2025
Division of Human Genetics, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa; McKusick-Nathans Institute, and Department of Genetic Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, USA. Electronic address:
Article Synopsis
- *This study focused on the genetic causes of HI in the Malian population through whole exome sequencing, uncovering variants in multiple known HI genes and identifying a novel candidate gene, UBFD1.
- *Results showed that 75% of the examined families had identifiable causes for HI, with many variants being newly identified and a case of digenic inheritance observed.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!