Splice-site mutations in the TRIC gene underlie autosomal recessive nonsyndromic hearing impairment in Pakistani families

Chishti, Muhammad Salman; Bhatti, Attya; Tamim, Sana; Lee, Kwanghyuk; McDonald, Merry-Lynn; Leal, Suzanne M.; Ahmad, Wasim

doi:10.1007/s10038-007-0209-3

Cited by 51 publications

(52 citation statements)

References 15 publications

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“…In the previous studies, the affected members of the DFNB49 families did not reveal any other obvious phenotypes besides prelingual, sensorineural hearing loss (24,28,29). However, the human families were not assessed to the same extent as the phenotypic evaluation of the tricellulin mutant mice.…”

Section: Figurementioning

confidence: 87%

“…Five different mutations in TRIC, encoding tricellulin, have been reported to cause autosomal recessive nonsyndromic deafness, DFNB49, in 14 families from Pakistan and Czech Roma populations (24,28,29). To determine the function of tricellulin in the inner ear and to elucidate the mechanism leading to hearing loss in the human families, we generated the corresponding knockin mouse model (p.Arg497*) for the only coding DFNB49 mutation (p.Arg500*).…”

Section: Introductionmentioning

confidence: 99%

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Tricellulin deficiency affects tight junction architecture and cochlear hair cells

Nayak¹,

Lee²,

Yousaf³

et al. 2013

J. Clin. Invest.

118

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The two compositionally distinct extracellular cochlear fluids, endolymph and perilymph, are separated by tight junctions that outline the scala media and reticular lamina. Mutations in TRIC (also known as MARVELD2), which encodes a tricellular tight junction protein known as tricellulin, lead to nonsyndromic hearing loss (DFNB49). We generated a knockin mouse that carries a mutation orthologous to the TRIC coding mutation linked to DFNB49 hearing loss in humans. Tricellulin was absent from the tricellular junctions in the inner ear epithelia of the mutant animals, which developed rapidly progressing hearing loss accompanied by loss of mechanosensory cochlear hair cells, while the endocochlear potential and paracellular permeability of a biotin-based tracer in the stria vascularis were unaltered. Freeze-fracture electron microscopy revealed disruption of the strands of intramembrane particles connecting bicellular and tricellular junctions in the inner ear epithelia of tricellulin-deficient mice. These ultrastructural changes may selectively affect the paracellular permeability of ions or small molecules, resulting in a toxic microenvironment for cochlear hair cells. Consistent with this hypothesis, hair cell loss was rescued in tricellulin-deficient mice when generation of normal endolymph was inhibited by a concomitant deletion of the transcription factor, Pou3f4. Finally, comprehensive phenotypic screening showed a broader pathological phenotype in the mutant mice, which highlights the non-redundant roles played by tricellulin.

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Section: Figurementioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Tricellulin deficiency affects tight junction architecture and cochlear hair cells

Nayak¹,

Lee²,

Yousaf³

et al. 2013

J. Clin. Invest.

118

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show abstract

“…Thus, tricellulin is required for maintenance of the tTJ barrier function. Moreover, tricellulin was reported to be the causative gene for a familial nonsyndromic deafness, DFNB49 (MIM 610153) (Chishti et al, 2008;Riazuddin et al, 2006). LSR is a type I transmembrane protein that was recently identified as a tTJ-localizing protein by localization-based expression cloning (Masuda et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Analysis of the angulin family consisting of LSR, ILDR1 and ILDR2: tricellulin recruitment, epithelial barrier function and implication in deafness pathogenesis

Higashi

Tokuda

Kitajiri

et al. 2012

Journal of Cell Science

178

227

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SummaryTricellular tight junctions (tTJs) seal the extracellular space at tricellular contacts (TCs), where the corners of three epithelial cells meet. To date, the transmembrane proteins tricellulin and lipolysis-stimulated lipoprotein receptor (LSR) are known to be molecular components of tTJs. LSR recruits tricellulin to tTJs, and both proteins are required for the full barrier function of epithelial cellular sheets. In the present study, we show that two LSR-related proteins, immunoglobulin-like domain-containing receptor (ILDR) 1 and ILDR2, are also localized at TCs and recruit tricellulin. At least one of LSR, ILDR1 and ILDR2 was expressed in most of the epithelial tissues in mice. The expressions of LSR, ILDR1 and ILDR2 were generally complementary to each other, although LSR and ILDR1 were co-expressed in some epithelia. ILDR1 was required for the establishment of a strong barrier of the epithelium, similar to LSR, when introduced into cultured epithelial cells, whereas ILDR2 provided a much weaker barrier. We further analyzed human ILDR1, mutations in which cause a familial deafness, DFNB42, and found that most DFNB42-associated ILDR1 mutant proteins were defective in recruitment of tricellulin. We also found that tricellulin mutant proteins associated with another familial deafness, DFNB49, were not recruited to TCs by ILDR1. These findings show the heterogeneity of the molecular organization of tTJs in terms of the content of LSR, ILDR1 or ILDR2, and suggest that ILDR1-mediated recruitment of tricellulin to TCs is required for hearing. Given their common localization at epithelial cell corners and recruitment of tricellulin, we propose to designate LSR, ILDR1 and ILDR2 as angulin family proteins.

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“…It contains seven exons and has a C-terminal ELL sequence with an overall identity of 32% (51% similarity) to occludin. Mutations of TRIC-a lead to nonsyndromic deafness, DFNB49 (Riazuddin et al, 2006;Chishti et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Tricellulin Forms a Barrier to Macromolecules in Tricellular Tight Junctions without Affecting Ion Permeability

Krug

Amasheh

Richter

et al. 2009

MBoC

308

322

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Tricellulin is a tight junction protein localized in tricellular tight junctions (tTJs), the meeting points of three cells, but also in bicellular tight junctions (bTJs). To investigate its specific barrier functions in bTJs and tTJs, TRIC-a was expressed in low-level tricellulin-expressing cells, and MDCK II, either in all TJs or only in tTJs. When expressed in all TJs, tricellulin increased paracellular electrical resistance and decreased permeability to ions and larger solutes, which are associated with enhanced ultrastructural integrity of bTJs toward enhanced strand linearity. In tTJs in contrast, ultrastructure was unchanged and tricellulin minimized permeability to macromolecules but not to ions. This paradox is explained by properties of the tTJ central tube which is wide enough for passage of macromolecules, but too rare to contribute significantly to ion permeability. In conclusion, at low tricellulin expression the tTJ central tube forms a pathway for macromolecules. At higher expression, tricellulin forms a barrier in tTJs effective only for macromolecules and in bTJs for solutes of all sizes.

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Splice-site mutations in the TRIC gene underlie autosomal recessive nonsyndromic hearing impairment in Pakistani families

Cited by 51 publications

References 15 publications

Tricellulin deficiency affects tight junction architecture and cochlear hair cells

Tricellulin deficiency affects tight junction architecture and cochlear hair cells

Analysis of the angulin family consisting of LSR, ILDR1 and ILDR2: tricellulin recruitment, epithelial barrier function and implication in deafness pathogenesis

Tricellulin Forms a Barrier to Macromolecules in Tricellular Tight Junctions without Affecting Ion Permeability

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