Last update 19 Sep 2024

TMC1

Last update 19 Sep 2024

Basic Info

Synonyms

DFNA36, DFNB11, DFNB7

+ [4]

Introduction

Probable ion channel required for the normal function of cochlear hair cells.

Drugs associated with TMC1

Tmc gene therapy(Harvard Medical School)

Target

TMC1

Mechanism

TMC1 agonists

Active Org.

Harvard Medical School

Originator Org.

Harvard Medical School

Active Indication

Hearing Loss

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Tmc gene therapy(University of Virginia)

Target

TMC1

Mechanism

TMC1 inhibitors

Active Org.

University of Virginia

Originator Org.

University of Virginia

Active Indication

Hearing Loss

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

TMC1 gene base editing therapy(Broad Institute)

Target

TMC1

Mechanism

TMC1 modulators

Active Org.

The Broad Institute, Inc.

Originator Org.

The Broad Institute, Inc.

Active Indication

Hearing Loss

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with TMC1

100 Translational Medicine associated with TMC1

0 Patents (Medical) associated with TMC1

270

Literatures (Medical) associated with TMC1

01 Sep 2024·Neuron

Sequence variations and accessory proteins adapt TMC functions to distinct sensory modalities

Article

Author: Kang, Lijun ; Zhu, Linhui ; Zou, Wenjuan ; Müller, Ulrich ; Jiang, Qiang ; Li, Shitian ; Qiu, Xufeng

Transmembrane channel-like (TMC) proteins are expressed throughout the animal kingdom and are thought to encode components of ion channels. Mammals express eight TMCs (mTMC1-8), two of which (mTMC1 and mTMC2) are subunits of mechanotransduction channels. C. elegans expresses two TMCs (TMC-1 and TMC-2), which mediate mechanosensation, egg laying, and alkaline sensing. The mechanisms by which nematode TMCs contribute to such diverse physiological processes and their functional relationship to mammalian mTMCs is unclear. Here, we show that association with accessory proteins tunes nematode TMC-1 to divergent sensory functions. In addition, distinct TMC-1 domains enable touch and alkaline sensing. Strikingly, these domains are segregated in mammals between mTMC1 and mTMC3. Consistent with these findings, mammalian mTMC1 can mediate mechanosensation in nematodes, while mTMC3 can mediate alkaline sensation. We conclude that sequence diversification and association with accessory proteins has led to the emergence of TMC protein complexes with diverse properties and physiological functions.

01 Jun 2024·Molecular Genetics & Genomic Medicine

Mutation spectrum of hearing loss patients in Northwest China: Identification of 20 novel variants

Article

Author: Zhang, Chuan ; Tian, Xinyuan ; Kang, Qichao ; Wu, Huiyan ; Hui, Ling ; Zhou, Bingbo ; Hao, Shengju ; Chen, Xue ; Ma, Panpan

AbstractBackgroundHearing loss (HL) is the most frequent sensory deficit in humans, with strong genetic heterogeneity. The genetic diagnosis of HL is very important to aid treatment decisions and to provide prognostic information and genetic counselling for the patient's family.MethodsWe detected and analysed 362 Chinese non‐syndromic HL patients by screening of variants in 15 hot spot mutations. Subsequently, 40 patients underwent further whole‐exome sequencing (WES) to determine genetic aetiology. The candidate variants were verified using Sanger sequencing. Twenty‐three carrier couples with pathogenic variants or likely pathogenic variants chose to proceed with prenatal diagnosis using Sanger sequencing.ResultsAmong the 362 HL patients, 102 were assigned a molecular diagnosis with 52 different variants in 22 deafness genes. A total of 41 (11.33%) cases with the biallelic GJB2 (OMIM # 220290) gene mutations were detected, and 21 (5.80%) had biallelic SLC26A4 (OMIM # 605646) mutations. Mitochondrial gene (OMIM # 561000) mutations were detected in seven (1.93%) patients. Twenty of the variants in 15 deafness genes were novel. SOX10 (OMIM # 602229), MYO15A (OMIM # 602666) and WFS1 (OMIM # 606201) were each detected in two patients. Meanwhile, OSBPL2 (OMIM # 606731), RRM2B (OMIM # 604712), OTOG (OMIM # 604487), STRC (OMIM # 606440), PCDH15 (OMIM # 605514), LOXHD1 (OMIM # 613072), CDH23 (OMIM # 605516), TMC1 (OMIM # 606706), CHD7 (OMIM # 608892), DIAPH3 (OMIM # 614567), TBC1D24 (OMIM # 613577), TIMM8A (OMIM # 300356), PTPRQ (OMIM # 603317), SALL1 (OMIM # 602218), and GSDME (OMIM # 608798) were each detected in one patient. In addition, as regards one couple with a heterozygous variant of CDH23 and PCDH15, respectively, prenatal diagnosis results suggest that the foetus had double heterozygous (DH) variants of CDH23 and PCDH15, which has a high risk to cause ID/F type Usher syndrome.ConclusionOur study expanded the spectrum of deafness gene variation, which will contribute to the genetic diagnosis, prenatal diagnosis and the procreation guidance of deaf couple. In addition, the deafness caused by two genes should be paid attention to in the prenatal diagnosis of families with both deaf patients.

01 Jun 2024·Hearing Research

Susceptibility of mouse cochlear hair cells to cisplatin ototoxicity largely depends on sensory mechanoelectrical transduction channels both Ex Vivo and In Vivo

Article

Author: Nishio, Ayako ; Tsutsumi, Takeshi ; Makabe, Ayane ; Kawashima, Yoshiyuki ; Fukunaga, Yoko ; Maruyama, Ayako

Cisplatin, a highly effective chemotherapeutic drug for various human cancers, induces irreversible sensorineural hearing loss as a side effect. Currently there are no highly effective clinical strategies for the prevention of cisplatin-induced ototoxicity. Previous studies have indicated that short-term cisplatin ototoxicity primarily affects the outer hair cells of the cochlea. Therefore, preventing the entry of cisplatin into hair cells may be a promising strategy to prevent cisplatin ototoxicity. This study aimed to investigate the entry route of cisplatin into mouse cochlear hair cells. The competitive inhibitor of organic cation transporter 2 (OCT2), cimetidine, and the sensory mechanoelectrical transduction (MET) channel blocker benzamil, demonstrated a protective effect against cisplatin toxicity in hair cells in cochlear explants. Sensory MET-deficient hair cells explanted from Tmc1^Δ;Tmc2^Δ mice were resistant to cisplatin toxicity. Cimetidine showed an additive protective effect against cisplatin toxicity in sensory MET-deficient hair cells. However, in the apical turn, cimetidine, benzamil, or genetic ablation of sensory MET channels showed limited protective effects, implying the presence of other entry routes for cisplatin to enter the hair cells in the apical turn. Systemic administration of cimetidine failed to protect cochlear hair cells from ototoxicity caused by systemically administered cisplatin. Notably, outer hair cells in MET-deficient mice exhibited no apparent deterioration after systemic administration of cisplatin, whereas the outer hair cells in wild-type mice showed remarkable deterioration. The susceptibility of mouse cochlear hair cells to cisplatin ototoxicity largely depends on the sensory MET channel both ex vivo and in vivo. This result justifies the development of new pharmaceuticals, such as a specific antagonists for sensory MET channels or custom-designed cisplatin analogs which are impermeable to sensory MET channels.

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TMC1

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