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Description: Explore known diseases related to classified transporter systems
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TCID System Name Disease OMIM

The 14 subunit vacuolar H+-ATPase, V1/V0, has been implicated in various human diseases including osteopetrosis, renal tubule acidosis, and cancer (Hinton et al., 2009).  The transmembrane enzyme, Ribonuclease kappa, RNASEK (137 aas; 2 TMSs; UniProt acc# Q6P5S7), closely associates with the V-ATPase and is required for its function; its loss prevents the early events of endocytosis and the replication of multiple pathogenic viruses (Perreira et al. 2015).  Cryo-EM allowed the construction of an atomic model, defining the enzyme's ATP:proton ratio as 3:10 and revealing a homolog of yeast subunit f in the membrane region, which appeared to be RNAseK (Abbas et al. 2020). The c ring encloses the transmembrane anchors for cleaved ATP6AP1/Ac45 and ATP6AP2/PRR, the latter of which is the (pro)renin receptor that, in other contexts, is involved in both Wnt signaling and the renin-angiotensin system that regulates blood pressure. This structure shows how ATP6AP1/Ac45 and ATP6AP2/PRR enable assembly of the enzyme's catalytic and membrane regions (Abbas et al. 2020). V-ATPase inhibitors, concanamycin and indole pentadiene, inhibit the enzyme by entry through the lipid membrane (Páli et al. 2004). ATP6V1, subunit H deficiency impairs glucose tolerance by augmenting endoplasmic reticulum stress in high fat diet fed mice (Yang et al. 2022). Defective lysosomal acidification provides a prognostic marker and therapeutic target for neurodegenerative diseases (Lo and Zeng 2023).  Variants in ATP6V1B2 are related to a heterogeneous group of multisystemic disorders sometimes associated with variable neurological involvement, including developmental epileptic encephalopathies (Amore et al. 2023). The subunit, ATP6V0A4 is a potential biomarker in renal cell carcinoma (Xu et al. 2023).

Renal tubular acidosis, distal, with progressive nerve deafness (dRTA-D) 267300

Heteromeric connexin (Cx)32/Cx26; (CxB2, GJβ2, GJB2) (transports cAMP, cGMP and all inositol phosphates with 1-4 esterified phosphate groups (homomeric Cx26(β2) or homomeric Cx32 do not transport the inositol phosphates as well) (Ayad et al., 2006). The GJB2 gene encodes connexin 26, the protein involved in cell-cell attachment in many tissues. GJB2 mutations cause autosomal recessive (DFNB1) and sometimes dominant (DFNA3) non-syndromic sensorineural hearing loss as well as various skin disease phenotypes (Iossa et al., 2011; Tian et al. 2022). TMS1 regulates oligomerization and function (Jara et al., 2012).  The carboxyl tail pg Cx32 regulates gap junction assembly (Katoch et al. 2015).  In Cx46, neutralization of negative charges or addition of positive charge in the Cx26 equivalent region reduced the slow gate voltage dependence. In Cx50 the addition of a glutamate in the same region decreased the voltage dependence and the neutralization of a negative charge increased it. Thus, the charges at the end of TMS1 are part of the slow gate voltage sensor in Cxs. The fact that Cx42, which has no charge in this region, still presents voltage dependent slow gating suggests that charges still unidentified also contribute to the slow gate voltage sensitivity (Pinto et al. 2016).  Syndromic deafness mutations at Asn14 alter the open stability of Cx26 hemichannels (Sanchez et al. 2016). The Leu89Pro substitution in the second TMS of CX32 disrupts the trafficking of the protein, inhibiting the assembly of CX32 gap junctions, which in turn may result in peripheral neuropathy (Da et al. 2016).  Cx26 mutants that promote cell death or exert transdominant effects on other connexins in keratinocytes lead to skin diseases and hearing loss, whereas mutants having reduced channel function without aberrant effects on coexpressed connexins cause only hearing loss (Press et al. 2017). When challenged by a field of 0.06 V/nm, the Cx26 hemichannel relaxed toward a novel configuration characterized by a widened pore and an increased bending of the second TMS at the level of the conserved Pro87. A point mutation that inhibited such a transition impeded hemichannel opening in electrophysiology and dye uptake experiments.  Thus, the Cx26 hemichannel uses a global degree of freedom to transit between different configuration states, which may be shared among all connexins (Zonta et al. 2018). A group of human mutations within the N-terminal (NT) domain of connexin 26 hemichannels produce aberrant channel activity, which gives rise to deafness and skin disorders, including keratitis-ichthyosis-deafness (KID) syndrome. Structural and functional studies indicate that the NT domain of connexin hemichannels is folded into the pore, where it plays important roles in permeability and gating. The mutation, N14K disrupts cytosolic intersubunit interactions and promotes channel opening (Valdez Capuccino et al. 2018). A missense mutation in the Connexin 26 gene is associated with hereditary autosomal recessive sensorineural deafness (Leshinsky-Silver et al. 2005, Zytsar et al. 2020). Cx26 hemichannels mediate the passage of contents between the cytoplasm and extracellular space. To generate hemichannels, the mutation N176Y was introduced into the second extracellular loop of Cx26. The cryoEM structure of the hexameric hemichannel in lipid bilayer nanodiscs displays an open pore and a 4-helix bundle transmembrane design that is nearly identical to dodecameric GJCs. In contrast to the high resolution of the transmembrane alpha-helices, the extracellular loops are less well resolved. The conformational flexibility of the extracellular loops may be essential to facilitate surveillance of hemichannels in apposed cells to identify compatible Cx isoforms that enable intercellular docking (Khan et al. 2021). A rare variant c.516G>C (p.Trp172Cys) in the GJB2 (connexin 26) gene is associated with nonsyndromic hearing loss (Maslova et al. 2021). Keratitis-ichthyosis-deafness (KID) syndrome is caused by mutations in the GJB2 gene  (Asgari et al. 2020). An increase in the partial pressure of carbon dioxide (PCO2) has been shown to cause Cx26 gap junctions to close. Cryo-EM was used to determine the structure of human Cx26 gap junctions under increasing levels of PCO2Brotherton et al. 2022 showed a correlation between the level of PCO2 and the size of the aperture of the pore, governed by the N-terminal helices that line the pore. Thus, CO2 alone is sufficient to cause conformational changes in the protein. Analysis of the conformational states showed that movements at the N-terminus are linked to both subunit rotation and flexing of the transmembrane helices (Brotherton et al. 2022). Cysteine residues in the C-terminal tail of connexin32 regulate its trafficking (Ray and Mehta 2021). The pathogenesis of common Gjb2 mutations are associated with human hereditary deafness (Li et al. 2023). Pan-cancer analysis of the prognostic and immunological role of GJB2 identifies a potential target for survival and immunotherapy (Jia et al. 2023).  The keratitis-ichthyosis-deafness (KID) syndrome is a rare genetic disease caused by pathogenic variants in connexin 26 (gene GJB2), which is a transmembrane channel of the epithelia (López-Sundh et al. 2023).  Consequences of pathogenic variants of the GJB2 gene (Cx26) localized in different Cx26 domains have been evaluated (Posukh et al. 2023).

Deafness, autosomal recessive, 1A (DFNB1A) 220290

6 TMS cell volume sensitive, voltage-gated K+ channel, KCNQ4 or Kv7.4 (mutations cause DFNA2, an autosomal dominant form of progressive hearing loss) (forms homomers or heteromers with KCNQ3) (localized to the basal membrane of cochlear outer hair cells and in several nuclei of the central auditory pathway in the brainstem). Four splice variants form heterotetramers; each subunit has different voltage and calmodulin-sensitivities (Xu et al., 2007).  Autosomal dominant mutant forms leading to progressive hearing loss (DFNA2) have been characterized (Kim et al. 2011). Phosphatidylinositol 4,5-bisphosphate (PIP2) and polyunsaturated fatty acids (PUFAs) impact ion channel function (Taylor and Sanders 2016). This channel may be present in mitochondria (Parrasia et al. 2019). Polyunsaturated fatty acids are modulators of KV7 channels (Larsson et al. 2020). The pathogenicity classification of KCNQ4 missense variants in clinical genetic testing has been described (Zheng et al. 2022). KCNQ4 potassium channel subunit deletion leads to exaggerated acoustic startle reflex in mice (Maamrah et al. 2023).

Deafness, autosomal dominant, 2A (DFNA2A) 600101

Boron transporter, NcBC1 or BTR1 or SLC4a11. In the absence of borate, it functions as a Na+ and OH- (H+) channel. In the presence of borate, it functions as an electrogenic Na+-coupled borate cotransporter (Park et al., 2004).  Three genetic corneal dystrophies (congenital hereditary endothelial dystrophy type 2 (CHED2), Harboyan syndrome and Fuchs endothelial corneal dystrophy (FECD) arise from mutations of the SLC4a11 gene, which cause blindness from fluid accumulation in the corneal stroma.  It can mediate water flux at a rate comparable to aquaporin in a process that is independent of solute transport (Vilas et al. 2013).  The systm has been reviewed by Patel and Parker 2015.  A 3-d homology model rationalizes various pathology-causing mutations (Badior et al. 2016). SLC4A11 is also a cell adhesion molecule involving extracellular loop 3, and cell adhesion defects contribute to FECD and CHED pathology (Malhotra et al. 2019). pH-dependence of Slc4a11-mediated H+ conductance is influenced by intracellular lysine residues and modified by disease-linked mutations (Quade et al. 2020). Corneal dystrophy mutations R125H and R804H disable SLC4A11 by altering the extracellular pH dependence of the intracellular pK that governs H+/OH- transport  (Quade et al. 2022).  Structural insights into the conformational changes of BTR1/SLC4A11 in complex with PIP(2) have been described (Lu et al. 2023).

Corneal dystrophy and perceptive deafness (CDPD) 217400

Sperm-associated cation channel, CatSper2 with 530 aas and 6 TMSs; it is a voltage-gated calcium channel that plays a central role in calcium-dependent physiological responses essential for successful fertilization, such as sperm hyperactivation, acrosome reaction and chemotaxis towards the oocyte (Strünker et al. 2011). The CatSper calcium channel is indirectly activated by extracellular progesterone and prostaglandins following the sequence: progesterone > PGF1-alpha = PGE1 > PGA1 > PGE2 >> PGD2 (Lishko et al. 2011).

Deafness-infertility syndrome (DIS) 611102

Sec-SRP translocase complex. The BAP29 and BAP31 (also called BCAP31) proteins interact directly with the Sec translocon (Wilson & Barlowe et al., 2010).  SRP68 and SRP72 form a complex with SRP RNA and SRP19.  The SRP68 binding site for the RNA is a tetratricopeptide-like module that bends the RNA and inserts an arginine-rich helix into the major groove to open the conserved 5f RNA loop and remodel the RNA for protein translocation (Grotwinkel et al. 2014).  Sec31 (Sec 31L1; HSPC334; HSPC275) is an outer cage component of the coat protein complex II (COPII) machinery which is recruited to specialized regions of the ER, called ER exit sites (ERES), where it plays a central role in the early secretory pathway. Sec31 also interacts with ALG-2 (Programed cell death protein 6 (PDCD6)) and annexin A11 (AnxA11) (Shibata et al. 2015). The Sec61 translocon mediates poorly efficient membrane insertion of Arg-containing TMSs, but a combination of arginine snorkeling, bilayer deformation, and peptide tilting is sufficient to lower the penalty of Arg insertion to an extent that a hydrophobic TMS with a central Arg residue readily inserts into a membrane (Ulmschneider et al. 2017). Mycolactone is a bacterium-derived macrolide that blocks the biogenesis of a large array of secretory and integral transmembrane proteins through potent inhibition of the Sec61 translocon (Morel et al. 2018). The Sec61α subunit possesses an opening between TMS2b and TMS7, the lateral gate, that is the exit for signal sequences and TMSs of translocating polypeptides to the lipid bilayer (Kida and Sakaguchi 2018). BCAP31 (BAP31; 246 aas and 3 N-terminal TMSs) is an ER chaparone that plays a role in the export of secreted proteins in the ER as well as the recognition of abnormally folded protein for targeting to the ER associated-degradation (ERAD) pathway (Wakana et al. 2008). It also serves as a cargo receptor for the export of transmembrane proteins (Annaert et al. 1997). Sec61 is the target of the cytotoxic plant-derived compound, ipomoeassin F (see TC family 8.C.10).Two accessory proteins of the Sec system are TRAP1 (of humans) and TRAM1 (of mice) (Shao 2023). The endoplasmic reticulum (ER) is a major site for protein synthesis, folding, and maturation in eukaryotic cells, responsible for production of secretory proteins and most integral membrane proteins. The universally conserved protein-conducting channel Sec61 complex mediates core steps in these processes by translocating hydrophilic polypeptide segments of client proteins across the ER membrane and integrating hydrophobic transmembrane segments into the membrane. The Sec61 complex associates with several other molecular machines and enzymes to enable substrate engagement with the channel and coordination of protein translocation with translation, protein folding, and/or post-translational modifications. Cryo-EM and functional studies have advanced our mechanistic understanding of Sec61-dependent protein biogenesis at the ER. Itskanov and Park 2022 reviewed current models for how Sec61 performs its functions in coordination with partner complexes. The SEC62 gene plays a role in dermato-oncology (Linxweiler and Müller 2022). The dynamic ribosome-translocon complex, which resides at the ER membrane, produces most of the human proteome. It governs the synthesis, translocation, membrane insertion, N-glycosylation, folding and disulfide-bond formation of nascent proteins. Gemmer et al. 2023  identified a pre-translocation intermediate with eukaryotic elongation factor 1a (eEF1a) in an extended conformation, suggesting that eEF1a may remain associated with the ribosome after GTP hydrolysis during proofreading. At the ER membrane, distinct polysomes bind to different ER translocons specialized in the synthesis of proteins with signal peptides or multipass TMSs with the translocon-associated protein complex (TRAP) present in both. The near-complete atomic model of the most abundant ER translocon variant, comprising the protein-conducting channel SEC61, TRAP and the oligosaccharyltransferase complex A (OSTA) revealed specific interactions of TRAP with other translocon components. Stoichiometric and sub-stoichiometric cofactors associated with OSTA were determined (Gemmer et al. 2023). Mycolactone B (not A) is an exotoxin produced by Mycobacterium ulcerans that causes the tropical skin disease, Buruli ulcer (Nguyen et al. 2023). This toxin inhibits the Sec61 translocon in the endoplasmic reticulum (ER), preventing the host cell from producing many secretory and transmembrane proteins. This results in cytotoxic and immunomodulatory effects. Isomer B's unique cytotoxicity is a consequence of both increased localization to the ER membrane and direct channel-locking association with the Sec61 translocon (Nguyen et al. 2023). To elucidate  redundancies in the components for the targeting of membrane proteins to the endoplasmic reticulum (ER) and/or their insertion into the ER membrane under physiological conditions, Jung and Zimmermann 2023 analyzed different human cells by label-free quantitative mass spectrometry. The HeLa and HEK293 cells had been depleted of a certain component by siRNA or CRISPR/Cas9 treatment or were deficient patient fibroblasts and compared to the respective control cells by differential protein abundance analysis. In addition to clients of the SRP and Sec61 complex, the authors identified membrane protein clients of components of the TRC/GET, SND, and PEX3 pathways for ER targeting, and Sec62, Sec63, TRAM1, and TRAP as putative auxiliary components of the Sec61 complex (Jung and Zimmermann 2023).  Most membrane proteins are synthesized on ER-bound ribosomes docked at the translocon. Sundaram et al. 2022 defined the composition, function and assembly of a translocon specialized for multipass membrane protein biogenesis. This 'multipass translocon' is distinguished by three components that selectively bind the ribosome-Sec61 complex during multipass protein synthesis: the GET- and EMC-like (GEL), protein associated with translocon (PAT) and back of Sec61 (BOS) complexes. Analysis of insertion intermediates revealed how features of the nascent chain trigger multipass translocon assembly. Reconstitution studies demonstrate a role for multipass translocon components in protein topogenesis, and cells lacking these components show reduced multipass protein stability, suggesting the mechanism by which nascent multipass proteins selectively recruit the multipass translocon to facilitate their biogenesis. They define the ER translocon as a dynamic assembly whose subunit composition adjusts co-translationally to accommodate the biosynthetic needs of its diverse range of substrates (Sundaram et al. 2022).  Intrinsically disordered region-mediated condensation of IFN-inducible SCOTIN/SHISA-5 inhibits ER-to-Golgi vesicle transport (Kim et al. 2023). The authors propose that SCOTIN impedes the ER-to-Golgi transport through its ability to form biomolecular condensates at the ER membrane.



Deafness, dystonia, and cerebral hypomyelination (DDCH) 300475

Prestin (Solute carrier family 26 member 5).  The motor protein responsible for the somatic electromotility of cochlear outer hair cells (OHC); essential for normal hearing sensitivity and frequency selectivity in mammals. Prestin transports a wide variety of monovalent and divalent anions. Many SulP transporters have C-terminal hydrophilic STAS domains that are essential for plasma membrane targeting and protein function. The crystal structure of this STAS domain has been solved at 1.57 Å resolution (Pasqualetto et al. 2010).  It senses voltage and binds anions for induction of conformational changes (He et al. 2013).  Prestin's 7+7 inverted repeat architecture suggests a central cavity as the substrate-binding site located midway within the anion permeation pathway. Anion binding to this site controls the electromotile activity of prestin (Gorbunov et al. 2014).  Zhai et al. 2020 studied the maturation of voltage-induced shifts in the Prestin operating point during trafficking. Calmodulin binds to the STAS domain with a calcium-dependent, one-lobe, binding mode (Costanzi et al. 2021). Prestin is the molecular actuator that drives OHC electromotility (eM). eM is mediated by an area motor mechanism, in which prestin proteins act as elementary actuators by changing their area in the membrane in response to changes in membrane potential. The area changes of a large and densely packed population of prestin molecules add up, resulting in macroscopic cellular movement. At the single protein level, this model implies major voltage-driven conformational rearrangements. SLC26 transporters including prestin generally are dimers. Lenz and Oliver 2021 reviewed the structures and discussed insights into a potential molecular mechanism. Distinct conformations were observed when purifying and imaging prestin bound to either its physiological ligand, chloride, or to competitively inhibitory anions, sulfate or salicylate. These structural snapshots indicate that the conformational landscape of prestin includes rearrangements between the two major domains of prestin's transmembrane region (TMD), core and scaffold ('gate') domains. Distinct conformations differ in the area the TMD occupies in the membrane and in their impact on the immediate lipid environment. Both effects can contribute to the generation of membrane deformation and thus may underly electromotility. Possibly, these or similar structural rearrangements are driven by the membrane potential to mediate piezoelectric activity (Lenz and Oliver 2021). Prestin differs from other Slc26 family members due to its unique piezoelectric-like property that drives OHC electromotility, the putative mechanism for cochlear amplification. Butan et al. 2022 used cryo-EM to determine prestin's structure at 3.6 Å resolution. Prestin was captured in an inward-open state which may reflect prestin's contracted state. Two well-separated transmembrane (TM) domains and two cytoplasmic sulfate transporter and anti-sigma factor antagonist (STAS) domains form a swapped dimer. The TM domains consist of 14 TMSs in two 7+7 inverted repeats, an architecture first observed in the bacterial symporter UraA. Mutation of prestin's chloride binding site removes salicylate competition with anions while retaining the prestin characteristic displacement currents (Nonlinear Capacitance), undermining the extrinsic voltage sensor hypothesis for prestin function (Butan et al. 2022). A structure-based mechanism for the membrane motor prestin has been presented (Ge et al. 2021). A novel role of the folding equilibrium of the anion-binding site in defining prestin's unique voltage-sensing mechanism and electromotility has been proposed (Lin et al. 2023).

Deafness, autosomal recessive, 61 (DFNB61) 613865
Vesicular glutamate transporter 3 (VGluT3) (Solute carrier family 17 member 8). Loss in mice produces circadian-dependent hyperdopaminergia and amiliorates motor disfunction and dopa-mediated dyskinesias in a model of Parkinson's Disease (Divito et al. 2015). VGLUT3 is expressed selectively in the inner hair cells (IHCs) and transports the neurotransmitter glutamate into synaptic vesicles. Mutation of the SLC17A8 gene is associated with DFNA25 (deafness, autosomal dominant 25), a non-syndromic hearing loss (ADNSHL) in humans (Ryu et al. 2016). Glut3 contributes to stress response and related psychopathologies (Horváth et al. 2018). An adeno-associated virus carrying the Slc17a8 gene restored vesicular Glut3 in the inner hair cells of the cochlea, thereby rescuing loss in mice that lacked Glut3 (Mathiesen et al. 2023).
Deafness, autosomal dominant, 25 (DFNA25) 605583

The transmembrane inner ear expressed protein, TMIE (156aas; 2 TMSs) (Fettiplace 2016).

Deafness, autosomal recessive, 6 (DFNB6) 600971

The tetraspan 24 protein, TSPAN24 or CD151 of 254 aas and 4 TMSs in a 3 + 1 TM arrangement.  It is essential for the proper assembly of the glomerular and tubular basement membranes in kidney, and also functions in egg-sperm interactions, possibly in cell-cell fusion, where oocyte CD151 interacts with CD49 in the sperm (Sabetian et al. 2014).

Nephropathy with pretibial epidermolysis bullosa and deafness (NPEBD) 609057

Mechanotransduction channel complex of cochlear hair cells TMHS/LHFPL5 is encoded by the Lhfpl5 gene.  The complex contains several proteins:  the tetraspan membrane protein of hair cell stereocilia, (TMHS protein) or Lipoma HMGIC fusion partner-like 5 protein (LHFPL5) (Fettiplace 2016), the Protocadherin-15 protein, PCDH15, and the Tmc1 and Tmc2 proteins (TC# 1.A.17) (Xiong et al. 2012).  TMHS and PCDH15 interact directly with Tmc1 and Tmc2, and these interactions are required for mechanotransduction (Maeda et al. 2014; Beurg et al. 2015). A primary function of Tmc1 may be calcium transport (Beurg et al. 2015).  Hair cells express two molecularly and functionally distinct mechanotransduction channels with different subcellular distributions. One is activated by sound and is responsible for sensory transduction. This sensory transduction channel is expressed in hair cell stereocilia, and its activity is affected by mutations in the genes encoding the transmembrane proteins TMHS (this family), TMIE (TC family 8.A.116), TMC1 and TMC2 (family 1.A.17.4) (Wu et al. 2016). Thus, these 4 proteins may all be parts of a single channel complex.  The other channel is the Piezo2 channel (TC# 1.A.75.1.2). TMHS is 68% identical to the human LHFPL3 protein (Q86UP9), and 62% identical to the human LHFPL4 protein (Q7Z7J7). The structure of protocadherin 15 with the tetraspan, LHFP5, has been determined (Ge et al. 2018). Deafness mutation D572N of TMC1 destabilizes TMC1 expression by disrupting LHFPL5 binding (Yu et al. 2020).

Deafness, autosomal recessive, 67 (DFNB67) 610265

MARVEL domain-containing protein 2, tricellulin, of 558 aas and 4 TMSs.  Plays a role in the formation of tight junctions in epithelial barriers. The separation of the endolymphatic and perilymphatic spaces of the organ of Corti from one another by epithelial barriers is required for normal hearing (Riazuddin et al. 2006).  Tricellulin forms tight junctions and is a junctional redox regulator (Cording et al. 2015).

Deafness, autosomal recessive, 49 (DFNB49) 610153

Alpha9/alpha10 (α9α10) neuronal acetylcholine receptor with the two subunits of 450 aas (α9; Chrna9 or NACHRA9) and 479 aas (α10; Chrna10 or NACHRA10). It is an ionotropic receptor with a probable role in the modulation of auditory stimuli. Agonist binding induces a conformation change that leads to the opening of an ion-conducting channel across the plasma membrane (Sgard et al. 2002, Zouridakis et al. 2014). The channel is permeable to a range of divalent cations including calcium, the influx of which may activate a potassium current which hyperpolarizes the cell membrane (Zouridakis et al. 2014). In the ear, this may lead to a reduction in basilar membrane motion, altering the activity of auditory nerve fibers and reducing the range of dynamic hearing. This may protect against acoustic trauma, and may also regulate keratinocyte adhesion (Nguyen et al. 2000). Hair cell alpha9alpha10 nicotinic acetylcholine receptor functional expression is regulated by ligand binding and deafness gene products (Gu et al. 2020). Auditory hair cells receive olivocochlear efferent innervation, which refines tonotopic mapping, improves sound discrimination, and mitigates acoustic trauma. The olivocochlear synapse involves α9α10nAChRs which assemble in hair cells only coincident with cholinergic innervation and do not express in recombinant mammalian cell lines. Genome-wide screening determined that assembly and surface expression of α9α10 require ligand binding. Ion channel function additionally demands an auxiliary subunit, which can be transmembrane inner ear (TMIE) or TMEM132e. Both of these single-pass transmembrane proteins are enriched in hair cells and underlie nonsyndromic human deafness. Inner hair cells from TMIE mutant mice show altered postsynaptic α9α10 function and retain α9α10-mediated transmission beyond the second postnatal week associated with abnormally persistent cholinergic innervation. Thus, the mechanism links cholinergic input with α9α10 assembly, identifies functions for human deafness genes TMIE/TMEM132e, and enables drug discovery for this elusive nAChR implicated in prevalent auditory disorders (Gu et al. 2020).  Point mutations in the nicotinic receptor alpha1 subunit can be responsible for slow-channel myasthenia (Kudryavtsev et al. 2021).


Deafness, autosomal recessive, 6 (DFNB6) 600971
Developed by Vamsee Reddy, 2015