Transmembrane channel-like protein 1 is a
protein that in humans is encoded by the ''TMC1''
gene.
TMC1 contains six transmembrane domains with both the C and N termini on the endoplasmic side of the membrane, as well as a large loop between domains 4 and 5. This topology is similar to that of
transient receptor potential channels (TRPs),
a family of proteins involved in the perception of senses such as temperature, taste, pressure, and vision. TMC1 has been located in the post-natal mouse cochlea,
and knockouts for TMC1 and
TMC2 result in both auditory and vestibular deficits (hearing loss and balance issues) indicating TMC1 is a molecular part of auditory transduction.
Function
This gene is considered a member of a gene family predicted to encode
transmembrane
A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequentl ...
proteins. Until recently, the specific function of this gene was relatively unknown; it was only known to be required for normal function of
cochlear hair cells.
However, new research suggests that TMC1 interacts with
Tip link proteins
protocadherin 15
Protocadherin-15 is a protein that in humans is encoded by the ''PCDH15'' gene.
Function
This gene is a member of the cadherin superfamily. Family members encode integral membrane proteins that mediate calcium-dependent cell-cell adhesion. Th ...
and
cadherin 23 indicating that TMC1, along with
TMC2, are necessary proteins for
hair cell
Hair cells are the sensory receptors of both the auditory system and the vestibular system in the ears of all vertebrates, and in the lateral line organ of fishes. Through mechanotransduction, hair cells detect movement in their environment. ...
mechanotransduction.
Specifically, TMC1 and
TMC2 may be two pore-forming subunits of the channel that responds to tip link deflection in hair cells.
Due to its implication in cochlear hair cell function and its interaction with hair cell tip links, TMC1 is being mutated and manipulated in order to better understand the receptor while at the same time producing a molecular model for deafness. While deafness can arise at any stage of auditory processing, DFNA36 (a type of progressive hearing loss) and DFNB7/B11 (congenital hearing loss) have been specifically shown to arise from TMC1 mutations. DFNA36 results from a dominant missense mutation and DFNB7/B11 results from a recessive mutation.
Both have been modeled in mice, known as the Beethoven model and the dn model respectively.
The TMC1 gene is located on
chromosome 9
Chromosome 9 is one of the 23 pairs of chromosomes in humans. Humans normally have two copies of this chromosome, as they normally do with all chromosomes. Chromosome 9 spans about 138 million base pairs of nucleic acids (the building blocks of D ...
q31-q21, and the dominant mutation associated with DFNA36 occurs at amino acid 572
which suggests the importance of this amino acid in the overall function of TMC1. Now that TMC1 has been shown to interact with the tip link proteins PCDH15 and CDH23,
the next question may be whether or not amino acid 572 is necessary for TMC1 tip link interactions.
Researchers reported in 2015 that genetically deaf mice treated with TMC1
gene therapy
Gene therapy is a medical field which focuses on the genetic modification of cells to produce a therapeutic effect or the treatment of disease by repairing or reconstructing defective genetic material. The first attempt at modifying human DN ...
recovered some of their hearing.
Clinical significance
Mutations in this gene have been associated with progressive
postlingual hearing loss,
non syndromic deafness and profound
prelingual deafness
Prelingual deafness refers to deafness that occurs before learning speech or language. Speech and language typically begin to develop very early with infants saying their first words by age one. Therefore, prelingual deafness is considered to occur ...
.
TMC1 mutations are not associated with other symptoms or abnormalities, which is known as
Nonsyndromic hearing loss and indicates that TMC1 functions mainly in auditory sensation.
Additionally, recessive mutations of the gene result in both a loss of TMC1 function as well as profound deafness
indicating TMC1 function is necessary for the processing of auditory signals.
References
Further reading
*
*
*
*
*
*
{{refend