Carcinoembryonic antigen-related cell adhesion molecule 16 interacts with α-tectorin and is mutated in autosomal dominant hearing loss (DFNA4)

Zheng, Jing; Miller, Katharine; Yang, Tao; Hildebrand, Michael S.; Shearer, A. Eliot; DeLuca, Adam P.; Scheetz, Todd E.; Drummond, Jennifer; Scherer, Steve; Legan, P. Kevin; Goodyear, Richard J.; Richardson, Guy P.; Cheatham, Mary Ann; Smith, Richard J.H.; Dallos, Peter

doi:10.1073/pnas.1005842108

Cited by 98 publications

(94 citation statements)

References 38 publications

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“…This gene resides within the DFNA4 locus, 27,28 suggesting the possible contribution of this gene to deafness, even though the heterogeneity of this locus was reported subsequently. 29,30 By evaluating four families with cosegregating moderate SNHL and a MYH14 mutation, Donaudy et al 31 reported a substantial contribution of MYH14 mutations to hereditary SNHL. Interestingly, the MYH14 mutation occurred as a de novo alteration in one of the four families.…”

Section: Genetics In Medicine | Volume 17 | Number 11 | November 2015mentioning

confidence: 99%

Whole-exome sequencing reveals diverse modes of inheritance in sporadic mild to moderate sensorineural hearing loss in a pediatric population

Kim

Park

et al. 2015

Genetics in Medicine

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Purpose: This study was designed to delineate genetic contributions, if any, to sporadic forms of mild to moderate sensorineural hearing loss (SNHL) not related to GJB2 mutations (DFNB1) in a pediatric population. Methods:We recruited 11 non-DFNB1 simplex cases of mild to moderate SNHL in children. We applied whole-exome sequencing to all 11 probands. We used a filtering strategy assuming that de novo variants of known autosomal dominant (AD) deafness genes, biallelic mutations in autosomal recessive (AR) genes, monoallelic mutations in X chromosome genes for males, and digenic inheritance could be associated. Candidate variants first were prioritized with allele frequency in public databases and confirmed by a phase or a segregation test in each family. Additional information from the literature or public databases was used to identify strong candidate variants.Results: Strong candidate variants were detected in 5 of 11 probands (45.4%). A diverse mode of inheritance implicated the sporadic occurrence of the phenotype. AR mutations in OTOGL and SERPINB6 and digenic inheritance involving two deafness genes, GPR98 and PDZ7, were detected. A de novo AD mutation also was detected in TECTA and MYH14. No syndromic feature was detected in individuals with GPR98/PDZ7 or MYH14 variants in our cohort at this moment. Conclusion:Mild to moderate pediatric SNHL, even if sporadic, features a strong genetic etiology and can manifest via diverse modes of inheritance. In addition, a multidisciplinary approach should be used for a correct diagnosis. Genet Med advance online publication 26 February 2015

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Section: Genetics In Medicine | Volume 17 | Number 11 | November 2015mentioning

confidence: 99%

Whole-exome sequencing reveals diverse modes of inheritance in sporadic mild to moderate sensorineural hearing loss in a pediatric population

Kim

Park

et al. 2015

Genetics in Medicine

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“…Even though the stereocilia of the cochlear inner hair cells (IHCs) appear to be free standing (Lim 1971;Dallos et al 1972), the TM is also thought to facilitate their stimulation (Dallos et al 1972;Richardson et al 2008;Lukashkin et al 2010). The body of the TM contains collagen fibrils embedded in an unusual striated-sheet matrix, the major components of which are alpha and betatectorin (Tecta and Tectb, respectively) and Ceacam16 (Legan et al 1997;Zheng et al 2011;Kammerer et al 2012;Cheatham et al 2014). In the absence of functional Tecta, the TM becomes completely de-tached from the organ of Corti and the animals suffer a significant hearing loss (Legan et al 2000;MorenoPelayo et al 2008;Legan et al 2014).…”

Section: Introductionmentioning

confidence: 99%

Increased Spontaneous Otoacoustic Emissions in Mice with a Detached Tectorial Membrane

Cheatham¹,

Ahmad²,

Zhou³

et al. 2015

JARO

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Mutations in genes encoding tectorial membrane (TM) proteins are a significant cause of human hereditary hearing loss , and several mouse models have been developed to study the functional significance of this accessory structure in the mammalian cochlea. In this study, we use otoacoustic emissions (OAE), signals obtained from the ear canal that provide a measure of cochlear function, to characterize a mouse in which the TM is detached from the spiral limbus due to an absence of otoancorin (Otoa, Lukashkin et al. 2012). Our results demonstrate that spontaneous emissions (SOAE), sounds produced in the cochlea without stimulation, increase dramatically in mice with detached TMs even though their hearing sensitivity is reduced. This behavior is unusual because wild-type (WT) controls are rarely spontaneous emitters. SOAEs in mice lacking Otoa predominate around 7 kHz, which is much lower than in either WT animals when they generate SOAEs or in mutant mice in which the TM protein Ceacam16 is absent (Cheatham et al. 2014). Although both mutants lack Hensen's stripe, loss of this TM feature is only observed in regions coding frequencies greater than~15 kHz in WT mice so its loss cannot explain the low-frequency, de novo SOAEs observed in mice lacking Otoa. The fact that~80 % of mice lacking Otoa produce SOAEs even when they generate smaller distortion product OAEs suggests that the active process is still functioning in these mutants but the system(s) involved have become less stable due to alterations in TM structure.

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“…Several CEACAMs are expressed and anchored predominantly on the surfaces of epithelial, endothelial, lymphocyte, myeloid, and granulocyte cells. Certain CEACAMs, however, are expressed only on one cell type or tissue, including CEACAM3, CEACAM8, and CEACAM16, which are expressed on phagocytes, granulocytes, and in the inner ear, respectively (3)(4)(5). With distinct expression patterns and localizations, CEACAMs are typically observed to be involved in numerous and diverse cellular functions, including cell adhesion, proliferation, signaling, differentiation, tumor suppression, and survival (6)(7)(8)(9)(10).…”

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confidence: 99%

Diverse oligomeric states of CEACAM IgV domains

Bonsor

Guenther

Beadenkopf

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) comprise a large family of cell surface adhesion molecules that bind to themselves and other family members to carry out numerous cellular functions, including proliferation, signaling, differentiation, tumor suppression, and survival. They also play diverse and significant roles in immunity and infection. The formation of CEACAM oligomers is caused predominantly by interactions between their N-terminal IgV domains. Although X-ray crystal structures of CEACAM IgV domain homodimers have been described, how CEACAMs form heterodimers or remain monomers is poorly understood. To address this key aspect of CEACAM function, we determined the crystal structures of IgV domains that form a homodimeric CEACAM6 complex, monomeric CEACAM8, and a heterodimeric CEACAM6-CEACAM8 complex. To confirm and quantify these interactions in solution, we used analytical ultracentrifugation to measure the dimerization constants of CEACAM homodimers and isothermal titration calorimetry to determine the thermodynamic parameters and binding affinities of CEACAM heterodimers. We found the CEACAM6-CEACAM8 heterodimeric state to be substantially favored energetically relative to the CEACAM6 homodimer. Our data provide a molecular basis for the adoption of the diverse oligomeric states known to exist for CEACAMs and suggest ways in which CEACAM6 and CEACAM8 regulate the biological functions of one another, as well as of additional CEACAMs with which they interact, both in cis and in trans.CEACAM | X-ray crystallography | isothermal titration calorimetry | analytical ultracentrifugation

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Carcinoembryonic antigen-related cell adhesion molecule 16 interacts with α-tectorin and is mutated in autosomal dominant hearing loss (DFNA4)

Cited by 98 publications

References 38 publications

Whole-exome sequencing reveals diverse modes of inheritance in sporadic mild to moderate sensorineural hearing loss in a pediatric population

Whole-exome sequencing reveals diverse modes of inheritance in sporadic mild to moderate sensorineural hearing loss in a pediatric population

Increased Spontaneous Otoacoustic Emissions in Mice with a Detached Tectorial Membrane

Diverse oligomeric states of CEACAM IgV domains

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