<i>TMTC2</i> variant associated with sensorineural hearing loss and auditory neuropathy spectrum disorder in a family dyad

Guillen-Ahlers, Hector; Erbe, Christy B.; Chevalier, Frédéric D.; Montoya, María; Zimmerman, Kip D.; Langefeld, Carl D.; Olivier, Michael; Runge-Samuelson, Christina L.

doi:10.1002/mgg3.397

Cited by 15 publications

(15 citation statements)

References 35 publications

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“…This connection may extend to hearing loss in patients as well. In parallel with our work recently, a missense mutation (rs35725509; Val136Ile) in the human ortholog TMTC2 was linked to nonsyndromic sensorineural hearing loss both in a 6-generation family and in a cohort of unrelated individuals with SNHL (179 affected vs. 186 matched controls) (19,35). This mutation was also recently identified in another family dyad with hearing loss (35).…”

Section: Discussionsupporting

confidence: 74%

“…In parallel with our work recently, a missense mutation (rs35725509; Val136Ile) in the human ortholog TMTC2 was linked to nonsyndromic sensorineural hearing loss both in a 6-generation family and in a cohort of unrelated individuals with SNHL (179 affected vs. 186 matched controls) (19,35). This mutation was also recently identified in another family dyad with hearing loss (35). Inactivation of Tmtc4 in a recently published large-scale genomics manuscript concurrent with our work was confirmed by a separate group to result in hearing loss, linking this class of proteins more strongly to hearing impairment (36).…”

Section: Discussionsupporting

confidence: 65%

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Deletion of Tmtc4 activates the unfolded protein response and causes postnatal hearing loss

Li¹,

Akil²,

Rouse³

et al. 2018

Journal of Clinical Investigation

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Section: Discussionsupporting

confidence: 74%

Section: Discussionsupporting

confidence: 65%

Deletion of Tmtc4 activates the unfolded protein response and causes postnatal hearing loss

Li¹,

Akil²,

Rouse³

et al. 2018

Journal of Clinical Investigation

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“…The circular RNA circTMTC1 inhibits skeletal muscle satellite cell differentiation in chicken [ 12 ]. TMTC2 is associated with non-syndromic sensorineural hearing loss (SNHL; via both GWAS and FS [ 13 , 14 ]). TMTC2 interactions with certain miRNAs hint towards a role in Parkinson’s disease [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Conserved sequence motifs in human TMTC1, TMTC2, TMTC3, and TMTC4, new O-mannosyltransferases from the GT-C/PMT clan, are rationalized as ligand binding sites

et al. 2021

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Background The human proteins TMTC1, TMTC2, TMTC3 and TMTC4 have been experimentally shown to be components of a new O-mannosylation pathway. Their own mannosyl-transferase activity has been suspected but their actual enzymatic potential has not been demonstrated yet. So far, sequence analysis of TMTCs has been compromised by evolutionary sequence divergence within their membrane-embedded N-terminal region, sequence inaccuracies in the protein databases and the difficulty to interpret the large functional variety of known homologous proteins (mostly sugar transferases and some with known 3D structure). Results Evolutionary conserved molecular function among TMTCs is only possible with conserved membrane topology within their membrane-embedded N-terminal regions leading to the placement of homologous long intermittent loops at the same membrane side. Using this criterion, we demonstrate that all TMTCs have 11 transmembrane regions. The sequence segment homologous to Pfam model DUF1736 is actually just a loop between TM7 and TM8 that is located in the ER lumen and that contains a small hydrophobic, but not membrane-embedded helix. Not only do the membrane-embedded N-terminal regions of TMTCs share a common fold and 3D structural similarity with subgroups of GT-C sugar transferases. The conservation of residues critical for catalysis, for binding of a divalent metal ion and of the phosphate group of a lipid-linked sugar moiety throughout enzymatically and structurally well-studied GT-Cs and sequences of TMTCs indicates that TMTCs are actually sugar-transferring enzymes. We present credible 3D structural models of all four TMTCs (derived from their closest known homologues 5ezm/5f15) and find observed conserved sequence motifs rationalized as binding sites for a metal ion and for a dolichyl-phosphate-mannose moiety. Conclusions With the results from both careful sequence analysis and structural modelling, we can conclusively say that the TMTCs are enzymatically active sugar transferases belonging to the GT-C/PMT superfamily. The DUF1736 segment, the loop between TM7 and TM8, is critical for catalysis and lipid-linked sugar moiety binding. Together with the available indirect experimental data, we conclude that the TMTCs are not only part of an O-mannosylation pathway in the endoplasmic reticulum of upper eukaryotes but, actually, they are the sought mannosyl-transferases.

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“…O-Man glycosylation has emerged as a widespread modification among specific adhesion molecules and receptors of eukaryotic cells. The discovery of three independent biosynthetic pathways targeting distinct proteins at the cell surface, including α -DG, cadherins and plexins, clearly points to important biological roles for O-Man in human physiology (20), and this notion is further supported by the diverse and severe developmental phenotypes in patients with defects in O-Man biosynthesis (27,28,45,46).…”

Section: Discussionmentioning

confidence: 99%

Global view of domain-specific O-linked mannose glycosylation in glycoengineered cells

Povolo,

Tian,

Vakhrushev

et al. 2024

Preprint

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Protein O-linked mannose (O-Man) glycosylation is an evolutionary conserved post-translational modification (PTM) that fulfills important biological roles during embryonic development. Three non-redundant enzyme families, POMT1/POMT2, TMTC1-4 and TMEM260, selectively coordinate the initiation of protein O-Man glycosylation on distinct classes of transmembrane proteins, including alpha-dystroglycan, cadherins and plexin receptors. However, a systematic investigation of their substrate specificities is lacking, in part due to the ubiquitous expression of O-Man glycosyltransferases in cells, which precludes analysis of pathway-specific O-Man glycosylation on a proteome-wide scale. Here, we apply a targeted workflow for membrane glycoproteomics across five human cell lines to extensively map O-Man substrates and genetically deconstruct O-Man initiation by individual and combinatorial knock-out (KO) of O-Man glycosyltransferase genes. We established a human cell library for analysis of substrate specificities of individual O-Man initiation pathways by quantitative glycoproteomics. Our results identify 180 O-Man glycoproteins, demonstrate new protein targets for the POMT1/POMT2 pathway and show that TMTC1-4 and TMEM260 pathways widely target distinct Ig-like protein domains of plasma membrane proteins involved in cell-cell and cell-extracellular matrix interactions. The identification of O-Man on Ig-like folds adds further knowledge on the emerging concept of domain-specific O-Man glycosylation which opens for functional studies of O-Man glycosylated adhesion molecules and receptors.

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TMTC2 variant associated with sensorineural hearing loss and auditory neuropathy spectrum disorder in a family dyad

Cited by 15 publications

References 35 publications

Deletion of Tmtc4 activates the unfolded protein response and causes postnatal hearing loss

Deletion of Tmtc4 activates the unfolded protein response and causes postnatal hearing loss

Conserved sequence motifs in human TMTC1, TMTC2, TMTC3, and TMTC4, new O-mannosyltransferases from the GT-C/PMT clan, are rationalized as ligand binding sites

Global view of domain-specific O-linked mannose glycosylation in glycoengineered cells

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