8.A.143.  The TMEM132 (TMEM132) Family 

TMEM132 genes can be mutated to cause non-syndromic hearing loss, panic disorder and cancer. The full domain architecture of human TMEM132 family proteins, solved using in-depth sequence and structural analysis reveal them to be five previously unappreciated cell adhesion molecules whose domain architecture has an early holozoan origin prior to the emergence of choanoflagellates and metazoa. The extra-cellular portions of TMEM132 proteins contain five conserved domains including three tandem immunoglobulin domains, and a cohesin domain homologue, the first such domain found in animals. Thus a cellular adhesion function for the TMEM132 family, connecting the extracellular medium with the intracellular actin cytoskeleton has been suggested (Sanchez-Pulido and Ponting 2018). These proteins are large (~ 1000 residues) and have two TMSs, one at the N-terminus, and one near the C-terminus. Hair cell alpha9alpha10 nicotinic acetylcholine receptor functional expression is regulated by ligand binding and deafness gene products (Gu et al. 2020; see next paragraph).

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 (Gu et al. 2020). 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).


 

References:

Gu, S., D. Knowland, J.A. Matta, M.L. O''Carroll, W.B. Davini, M. Dhara, H.J. Kweon, and D.S. Bredt. (2020). Hair cell α9α10 nicotinic acetylcholine receptor functional expression regulated by ligand binding and deafness gene products. Proc. Natl. Acad. Sci. USA 117: 24534-24544.

Liu, H., J. Barnes, E. Pedrosa, N.S. Herman, F. Salas, P. Wang, D. Zheng, and H.M. Lachman. (2020). Transcriptome analysis of neural progenitor cells derived from Lowe syndrome induced pluripotent stem cells: identification of candidate genes for the neurodevelopmental and eye manifestations. J Neurodev Disord 12: 14.

Sanchez-Pulido, L. and C.P. Ponting. (2018). TMEM132: an ancient architecture of cohesin and immunoglobulin domains define a new family of neural adhesion molecules. Bioinformatics 34: 721-724.

Examples:

TC#NameOrganismal TypeExample
8.A.143.1.1

Transmembrane protein 132A, TMEM132A, of 1032 aas and 2 TMSs, N-terminal and near the C-terminus. It may play a role in embryonic and postnatal development of the brain. Increased resistance to cell death is induced by serum starvation in cultured cells. It regulates cAMP-induced GFAP gene expression via STAT3 phosphorylation (Sanchez-Pulido and Ponting 2018). It may play a role in Lowe syndrome (LS) (Liu et al. 2020).

TMEM132A of Homo sapiens

 
8.A.143.1.2

Transmembrane protein 132E, TMEM132E of 1610 aas and 2 - 4 TMSs.

TMEM132E of Danaus plexippus plexippus

 
8.A.143.1.3

Uncharacterized protein of 1176 aas and 1 TMS near the C-terminus.

UP of Helobdella robusta

 
8.A.143.1.4

Uncharacterized protein of 1948 aas and 2 TMSs, one at the N-terminus, and one near the C-terminus.

UP of Opisthorchis viverrini

 
8.A.143.1.5

TMEM132e of 1074 aas and 2 TMSs.  Ion channel function for the α9α10 nicotinic acetylcholine receptor (1.A.9.1.22) requires an auxiliary subunit, which can be transmembrane inner ear (TMIE; TC# 8.A,116) or TMEM132e. Both of these single-pass transmembrane proteins are enriched in hair cells and underlie nonsyndromic human deafness (Gu et al. 2020).

TMEM132e of Homo sapiens