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Ayala Lagziel

Publications and source records attributed to Ayala Lagziel.

8 recordsLinked to original sources
PubMed2006

Tricellulin is a tight-junction protein necessary for hearing.

The inner ear has fluid-filled compartments of different ionic compositions, including the endolymphatic and perilymphatic spaces of the organ of Corti; the separation from one another by epithelial barriers is required for normal hearing. TRIC encodes tricellulin, a recently discovered tight-junction (TJ) protein that contributes to the structure and function of tricellular contacts of neighboring cells in many epithelial tissues. We show that, in humans, four different recessive mutations of TRIC cause nonsyndromic deafness (DFNB49), a surprisingly limited phenotype, given the widespread tissue distribution of tricellulin in epithelial cells. In the inner ear, tricellulin is concentrated at the tricellular TJs in cochlear and vestibular epithelia, including the structurally complex and extensive junctions between supporting and hair cells. We also demonstrate that there are multiple alternatively spliced isoforms of TRIC in various tissues and that mutations of TRIC associated with hearing loss remove all or most of a conserved region in the cytosolic domain that binds to the cytosolic scaffolding protein ZO-1. A wild-type isoform of tricellulin, which lacks this conserved region, is unaffected by the mutant alleles and is hypothesized to be sufficient for structural and functional integrity of epithelial barriers outside the inner ear.

Alternative Splicing↗
PubMed2006

Signatures from tissue-specific MPSS libraries identify transcripts preferentially expressed in the mouse inner ear.

Specialization in cell function and morphology is influenced by the differential expression of mRNAs, many of which are expressed at low abundance and restricted to certain cell types. Detecting such transcripts in cDNA libraries may require sequencing millions of clones. Massively parallel signature sequencing (MPSS) is well suited to identifying transcripts that are expressed in discrete cell types and in low abundance. We have made MPSS libraries from microdissections of three inner ear tissues. By comparing these MPSS libraries to those of 87 other tissues included in the Mouse Reference Transcriptome online resource, we have identified genes that are highly enriched in, or specific to, the inner ear. We show by RT-PCR and in situ hybridization that signatures unique to the inner ear libraries identify transcripts with highly specific cell-type localizations. These transcripts serve to illustrate the utility of a resource that is available to the research community. Utilization of these resources will increase the number of known transcription units and expand our knowledge of the tissue-specific regulation of the transcriptome.

Animals↗
PubMed2006

The tip-link antigen, a protein associated with the transduction complex of sensory hair cells, is protocadherin-15.

Sound and acceleration are detected by hair bundles, mechanosensory structures located at the apical pole of hair cells in the inner ear. The different elements of the hair bundle, the stereocilia and a kinocilium, are interconnected by a variety of link types. One of these links, the tip link, connects the top of a shorter stereocilium with the lateral membrane of an adjacent taller stereocilium and may gate the mechanotransducer channel of the hair cell. Mass spectrometric and Western blot analyses identify the tip-link antigen, a hitherto unidentified antigen specifically associated with the tip and kinocilial links of sensory hair bundles in the inner ear and the ciliary calyx of photoreceptors in the eye, as an avian ortholog of human protocadherin-15, a product of the gene for the deaf/blindness Usher syndrome type 1F/DFNB23 locus. Multiple protocadherin-15 transcripts are shown to be expressed in the mouse inner ear, and these define four major isoform classes, two with entirely novel, previously unidentified cytoplasmic domains. Antibodies to the three cytoplasmic domain-containing isoform classes reveal that each has a different spatiotemporal expression pattern in the developing and mature inner ear. Two isoforms are distributed in a manner compatible for association with the tip-link complex. An isoform located at the tips of stereocilia is sensitive to calcium chelation and proteolysis with subtilisin and reappears at the tips of stereocilia as transduction recovers after the removal of calcium chelators. Protocadherin-15 is therefore associated with the tip-link complex and may be an integral component of this structure and/or required for its formation.

Animals↗
PubMed2005

Spatiotemporal pattern and isoforms of cadherin 23 in wild type and waltzer mice during inner ear hair cell development.

Mutant alleles of the gene encoding cadherin 23 are associated with Usher syndrome type 1 (USH1D), isolated deafness (DFNB12) in humans, and deafness and circling behavior in waltzer (v) mice. Stereocilia of waltzer mice are disorganized and the kinocilia misplaced, indicating the importance of cadherin 23 for hair bundle development. Cadherin 23 was localized to developing stereocilia and proposed as a component of the tip link. We show that, during development of the inner ear, cadherin 23 is initially detected in centrosomes at E14.5, then along the length of emerging stereocilia, and later becomes concentrated at and subsequently disappears from the tops of stereocilia. In mature vestibular hair bundles, cadherin 23 is present along the kinocilium and in the region of stereocilia-kinocilium bonds, a pattern conserved in mammals, chicks, and frogs. Cadherin 23 is also present in Reissner's membrane (RM) throughout development. In homozygous v(6J) mice, a reported null allele, cadherin 23 was absent from stereocilia, but present in kinocilia, RM, and centrosomes. We reconciled these results by identifying two novel isoforms of Cdh23 unaffected in sequence and expression by the v(6J) allele. Our results suggest that Cdh23 participation in stereocilia links may be restricted to developing hair bundles.

Alleles↗
PubMed2005

Modification of human hearing loss by plasma-membrane calcium pump PMCA2.

Five adult siblings presented with autosomal recessive sensorineural hearing loss: two had high-frequency loss, whereas the other three had severe-to-profound loss affecting all frequencies. Genetic evaluation revealed that a homozygous mutation in CDH23 (which encodes cadherin 23) caused the hearing loss in all five siblings and that a heterozygous, hypofunctional variant (V586M) in plasma-membrane calcium pump PMCA2, which is encoded by ATP2B2, was associated with increased loss in the three severely affected siblings. V586M was detected in two unrelated persons with increased sensorineural hearing loss, in the other caused by a mutation in MYO6 (which encodes myosin VI) in one and by noise exposure, suggesting that this variant may modify the severity of sensorineural hearing loss caused by a variety of factors.

Adult↗
PubMed2004

Warfarin therapy is feasible in CYP2C9*3 homozygous patients.

Background: Patients carrying variant CYP2C9 alleles are prone to bleeding complications under standard warfarin treatment. Our aim was to test the feasibility of warfarin therapy in patients with severe, inherited CYP2C9 deficiency. Methods: CYP2C9 genotypes and clinical characteristics were compared retrospectively in patients who maintain stable anticoagulation on low or regular doses of warfarin. Results: In the low-dose (10.5+/-2.9 mg/week) group (N=16), we identified six (37.6%) patients with severe CYP2C9 deficiency and three each with *2/*3 and *3/*3 genotypes as compared to none in the standard dose (39.2+/-17.9 mg/week) group (N=17). Warfarin dose (mg/week) was correlated with genotype in all patients as follows: *1/*1 (N=14) dose=33.6+/-19.4; *1/*2 (N=9) dose=30.4+/-21.6; *1/*3 (N=4) dose=15.3+/-10.7; *2/*3 (N=3) dose=10.6+/-3.6; *3/*3 (N=3) dose=7.3+/-3.1. Age and frequency of concurrent warfarin potentiating medication administration were higher in the low-dose group than in the standard dose group of patients. Conclusions: Warfarin treatment is feasible in individuals with severe, inherited CYP2C9 deficiency. Dose requirement was correlated with CYP2C9 genotype and possibly affected by age and concurrent intake of interfering drugs. Prospective studies are needed to test the feasibility and cost effectiveness of using algorithms based on these parameters for adjusting initial warfarin dose to meet individual needs.

Journal Article↗