TMTC1 and TMTC2 Are Novel Endoplasmic Reticulum Tetratricopeptide Repeat-containing Adapter Proteins Involved in Calcium Homeostasis

Sunryd, Johan C.; Cheon, Banyoon; Graham, Jill B.; Giorda, Kristina M.; Fissore, Rafael A.; Hebert, Daniel N.

doi:10.1074/jbc.m114.554071

Cited by 63 publications

(62 citation statements)

References 44 publications

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“…TMTC2 is expressed in many tissues (Wu, MacLeod, & Su, 2013) including the inner ear (Runge et al, 2016). While the specific function(s) of TMTC2 within the auditory system remain unknown, the protein is likely to affect ion currents and membrane potential in inner ear cells, based on reported functions in other cell types (Sunryd et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

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

Guillen-Ahlers

Erbe

Chevalier

et al. 2018

Molec Gen & Gen Med

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BackgroundSensorineural hearing loss (SNHL) is a common form of hearing loss that can be inherited or triggered by environmental insults; auditory neuropathy spectrum disorder (ANSD) is a SNHL subtype with unique diagnostic criteria. The genetic factors associated with these impairments are vast and diverse, but causal genetic factors are rarely characterized.MethodsA family dyad, both cochlear implant recipients, presented with a hearing history of bilateral, progressive SNHL, and ANSD. Whole‐exome sequencing was performed to identify coding sequence variants shared by both family members, and screened against genes relevant to hearing loss and variants known to be associated with SNHL and ANSD.ResultsBoth family members are successful cochlear implant users, demonstrating effective auditory nerve stimulation with their devices. Genetic analyses revealed a mutation (rs35725509) in the TMTC2 gene, which has been reported previously as a likely genetic cause of SNHL in another family of Northern European descent.ConclusionThis study represents the first confirmation of the rs35725509 variant in an independent family as a likely cause for the complex hearing loss phenotype (SNHL and ANSD) observed in this family dyad.

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Section: Discussionmentioning

confidence: 99%

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

Guillen-Ahlers

Erbe

Chevalier

et al. 2018

Molec Gen & Gen Med

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“…The motif is found in a number of proteins and mediates protein-protein interaction (http://www.uniprot.org/keywords/KW-0802). A previous study 20 localized TMTC2 to the endoplasmic reticulum in HEK293 cells and found it to be associated with the endoplasmic reticulum calcium uptake pump SERCA2B, but the detailed function of the protein and its putative role in other tissues have not been elucidated. It is possible that TMTC2 is involved in a novel mechanism that affects hearing in humans.…”

Section: Discussionmentioning

confidence: 99%

Association ofTMTC2With Human Nonsyndromic Sensorineural Hearing Loss

Runge-Samuelson

Indap

Zhou

et al. 2016

JAMA Otolaryngol Head Neck Surg

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IMPORTANCE Sensorineural hearing loss (SNHL) is commonly caused by conditions that affect cochlear structures or the auditory nerve, and the genes identified as causing SNHL to date only explain a fraction of the overall genetic risk for this debilitating disorder. It is likely that other genes and mutations also cause SNHL. OBJECTIVE To identify a candidate gene that causes bilateral, symmetric, progressive SNHL in a large multigeneration family of Northern European descent. DESIGN, SETTING, AND PARTICIPANTS In this prospective genotype and phenotype study performed from January 1, 2006, through April 1, 2016, a 6-generation family of Northern European descent with 19 individuals having reported early-onset hearing loss suggestive of an autosomal dominant inheritance were studied at a tertiary academic medical center. In addition, 179 unrelated adult individuals with SNHL and 186 adult individuals reporting nondeafness were examined. MAIN OUTCOMES AND MEASURES Sensorineural hearing loss. RESULTS Nine family members (5 women [55.6%]) provided clinical audiometric and medical records that documented hearing loss. The hearing loss is characterized as bilateral, symmetric, progressive SNHL that reached severe to profound loss in childhood. Audiometric configurations demonstrated a characteristic dip at 1000 to 2000 Hz. All affected family members wear hearing aids or have undergone cochlear implantation. Exome sequencing and linkage and association analyses identified a fully penetrant sequence variant (rs35725509) on chromosome 12q21 (logarithm of odds, 3.3) in the TMTC2 gene region that segregates with SNHL in this family. This gene explains the SNHL occurrence in this family. The variant is also associated with SNHL in a cohort of 363 unrelated individuals (179 patients with confirmed SNHL and 184 controls, P = 7 × 10−4). CONCLUSIONS AND RELEVANCE A previously uncharacterized gene, TMTC2, has been identified as a candidate for causing progressive SNHL in humans. This finding identifies a novel locus that causes autosomal dominant SNHL and therefore a more detailed understanding of the genetic basis of SNHL. Because TMTC2 has not been previously reported to regulate auditory function, the discovery reveals a potentially new, uncharacterized mechanism of hearing loss.

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“…TMTC3 and TMTC4 are present in the chordata phylum and recent analysis shows that they are conserved in protists (Larsen et al, 2019). Like TMTC1 and TMTC2, TMTC3 and TMTC4 are divided into two regions that appear to create distinct domains, an N-terminal hydrophobic region and a Cterminal domain consisting of large TPR clusters (Sunryd et al, 2014). ΔG predicts that TMTC3 and TMTC4 have ten and twelve potential transmembrane domains, respectively (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…A new putative family of O-mannosyltransferases was recently discovered in mammals (Larsen et al, 2017a(Larsen et al, , 2017b. This family is comprised of four tetratricopeptide repeat (TPR)-containing proteins that appear to be ER polytopic transmembrane proteins called TMTC1-4 (transmembrane and TPR-containing proteins 1-4) (Della-Morte et al, 2011;Racapé et al, 2011;Cao et al, 2012;Sunryd et al, 2014;Larsen et al, 2017a;Li et al, 2018). TMTC1, 2 and 4 are ER proteins involved in Ca 2+ regulation as they associate with ER Ca 2+ re-uptake pump SERCA2B (Sunryd et al, 2014;Li et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…This family is comprised of four tetratricopeptide repeat (TPR)-containing proteins that appear to be ER polytopic transmembrane proteins called TMTC1-4 (transmembrane and TPR-containing proteins 1-4) (Della-Morte et al, 2011;Racapé et al, 2011;Cao et al, 2012;Sunryd et al, 2014;Larsen et al, 2017a;Li et al, 2018). TMTC1, 2 and 4 are ER proteins involved in Ca 2+ regulation as they associate with ER Ca 2+ re-uptake pump SERCA2B (Sunryd et al, 2014;Li et al, 2018). The knockouts of TMTC1-4 have been shown using glycoproteomics to be involved in the O-mannosylation of cadherins (Larsen et al, 2017a(Larsen et al, , 2019.…”

Section: Introductionmentioning

confidence: 99%

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ER transmembrane protein TMTC3 contributes to O-mannosylation of E-cadherin, Cellular Adherence and Embryonic Gastrulation

Graham

Sunryd

Mathavan

et al. 2019

Preprint

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Protein glycosylation plays essential roles in protein structure, stability and activity such as cell adhesion. The cadherin superfamily of adhesion molecules carry O-linked mannose glycans at conserved sites and it was recently demonstrated that the TMTC1-4 genes contribute to the addition of these O-linked mannoses. Here, biochemical, cell biological and organismal analysis was used to determine that TMTC3 supports the Omannosylation of E-cadherin, cellular adhesion and embryonic gastrulation. Using genetically engineered cells lacking all four TMTC genes, overexpression of TMTC3 rescued O-linked glycosylation of E-cadherin and cell adherence. The knockdown of the Tmtcs in Xenopus laevis embryos caused a delay in gastrulation that was rescued by the addition of human TMTC3. Mutations in TMTC3 have been linked to neuronal cell migration diseases including Cobblestone lissencephaly. Analysis of TMTC3 mutations associated with Cobblestone lissencephaly found that three of the variants exhibit reduced stability and missence mutations were unable to complement TMTC3 rescue of gastrulation in Xenopus embryo development. Our study demonstrates that TMTC3 regulates O-linked glycosylation and cadherin-mediated adherence, providing insight into its effect on cellular adherence and migration, as well the basis of TMTC3associated Cobblestone lissencephaly.

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TMTC1 and TMTC2 Are Novel Endoplasmic Reticulum Tetratricopeptide Repeat-containing Adapter Proteins Involved in Calcium Homeostasis

Cited by 63 publications

References 44 publications

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

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

Association ofTMTC2With Human Nonsyndromic Sensorineural Hearing Loss

ER transmembrane protein TMTC3 contributes to O-mannosylation of E-cadherin, Cellular Adherence and Embryonic Gastrulation

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