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Three deaf mice: mouse models for TECTA-based human hereditary deafness reveal domain-specific structural phenotypes in the tectorial membrane
Tecta is a modular, non-collagenous protein of the tectorial membrane (TM), an extracellular matrix of the cochlea essential for normal hearing. Missense mutations in Tecta cause dominant forms of non-syndromic deafness and a genotype–phenotype correlation has been reported in humans, with mutations...
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Published in: | Human molecular genetics 2014-05, Vol.23 (10), p.2551-2568 |
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creator | Legan, P. Kevin Goodyear, Richard J. Morín, Matías Mencia, Angeles Pollard, Hilary Olavarrieta, Leticia Korchagina, Julia Modamio-Hoybjor, Silvia Mayo, Fernando Moreno, Felipe Moreno-Pelayo, Miguel-Angel Richardson, Guy P. |
description | Tecta is a modular, non-collagenous protein of the tectorial membrane (TM), an extracellular matrix of the cochlea essential for normal hearing. Missense mutations in Tecta cause dominant forms of non-syndromic deafness and a genotype–phenotype correlation has been reported in humans, with mutations in different Tecta domains causing mid- or high-frequency hearing impairments that are either stable or progressive. Three mutant mice were created as models for human Tecta mutations; the TectaL1820F,G1824D/+ mouse for zona pellucida (ZP) domain mutations causing stable mid-frequency hearing loss in a Belgian family, the TectaC1837G/+ mouse for a ZP-domain mutation underlying progressive mid-frequency hearing loss in a Spanish family and the TectaC1619S/+ mouse for a zonadhesin-like (ZA) domain mutation responsible for progressive, high-frequency hearing loss in a French family. Mutations in the ZP and ZA domains generate distinctly different changes in the structure of the TM. Auditory brainstem response thresholds in the 8–40 kHz range are elevated by 30–40 dB in the ZP-domain mutants, whilst those in the ZA-domain mutant are elevated by 20–30 dB. The phenotypes are stable and no evidence has been found for a progressive deterioration in TM structure or auditory function. Despite elevated auditory thresholds, the Tecta mutant mice all exhibit an enhanced tendency to have audiogenic seizures in response to white noise stimuli at low sound pressure levels (≤84 dB SPL), revealing a previously unrecognised consequence of Tecta mutations. These results, together with those from previous studies, establish an allelic series for Tecta unequivocally demonstrating an association between genotype and phenotype. |
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Kevin ; Goodyear, Richard J. ; Morín, Matías ; Mencia, Angeles ; Pollard, Hilary ; Olavarrieta, Leticia ; Korchagina, Julia ; Modamio-Hoybjor, Silvia ; Mayo, Fernando ; Moreno, Felipe ; Moreno-Pelayo, Miguel-Angel ; Richardson, Guy P.</creator><creatorcontrib>Legan, P. Kevin ; Goodyear, Richard J. ; Morín, Matías ; Mencia, Angeles ; Pollard, Hilary ; Olavarrieta, Leticia ; Korchagina, Julia ; Modamio-Hoybjor, Silvia ; Mayo, Fernando ; Moreno, Felipe ; Moreno-Pelayo, Miguel-Angel ; Richardson, Guy P.</creatorcontrib><description>Tecta is a modular, non-collagenous protein of the tectorial membrane (TM), an extracellular matrix of the cochlea essential for normal hearing. Missense mutations in Tecta cause dominant forms of non-syndromic deafness and a genotype–phenotype correlation has been reported in humans, with mutations in different Tecta domains causing mid- or high-frequency hearing impairments that are either stable or progressive. Three mutant mice were created as models for human Tecta mutations; the TectaL1820F,G1824D/+ mouse for zona pellucida (ZP) domain mutations causing stable mid-frequency hearing loss in a Belgian family, the TectaC1837G/+ mouse for a ZP-domain mutation underlying progressive mid-frequency hearing loss in a Spanish family and the TectaC1619S/+ mouse for a zonadhesin-like (ZA) domain mutation responsible for progressive, high-frequency hearing loss in a French family. Mutations in the ZP and ZA domains generate distinctly different changes in the structure of the TM. Auditory brainstem response thresholds in the 8–40 kHz range are elevated by 30–40 dB in the ZP-domain mutants, whilst those in the ZA-domain mutant are elevated by 20–30 dB. The phenotypes are stable and no evidence has been found for a progressive deterioration in TM structure or auditory function. Despite elevated auditory thresholds, the Tecta mutant mice all exhibit an enhanced tendency to have audiogenic seizures in response to white noise stimuli at low sound pressure levels (≤84 dB SPL), revealing a previously unrecognised consequence of Tecta mutations. These results, together with those from previous studies, establish an allelic series for Tecta unequivocally demonstrating an association between genotype and phenotype.</description><identifier>ISSN: 0964-6906</identifier><identifier>EISSN: 1460-2083</identifier><identifier>DOI: 10.1093/hmg/ddt646</identifier><identifier>PMID: 24363064</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Acoustic Stimulation ; Animals ; Deafness - genetics ; Deafness - pathology ; Deafness - physiopathology ; Disease Models, Animal ; Epilepsy, Reflex - genetics ; Extracellular Matrix Proteins - genetics ; Female ; Genetic Association Studies ; Genetic Predisposition to Disease ; GPI-Linked Proteins - genetics ; Hair Cells, Auditory, Inner - pathology ; Homozygote ; Humans ; Male ; Mice, 129 Strain ; Mice, Transgenic ; Molecular Motor Proteins - metabolism ; Mutation, Missense ; Organ of Corti - pathology ; Phenotype ; Tectorial Membrane - metabolism ; Tectorial Membrane - pathology</subject><ispartof>Human molecular genetics, 2014-05, Vol.23 (10), p.2551-2568</ispartof><rights>The Author 2013. Published by Oxford University Press. 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c441t-415e160234b77966cc092a093d216871717e5934e79ca8dd86e5e60975fe1443</citedby><cites>FETCH-LOGICAL-c441t-415e160234b77966cc092a093d216871717e5934e79ca8dd86e5e60975fe1443</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,786,790,891,1591,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24363064$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Legan, P. Kevin</creatorcontrib><creatorcontrib>Goodyear, Richard J.</creatorcontrib><creatorcontrib>Morín, Matías</creatorcontrib><creatorcontrib>Mencia, Angeles</creatorcontrib><creatorcontrib>Pollard, Hilary</creatorcontrib><creatorcontrib>Olavarrieta, Leticia</creatorcontrib><creatorcontrib>Korchagina, Julia</creatorcontrib><creatorcontrib>Modamio-Hoybjor, Silvia</creatorcontrib><creatorcontrib>Mayo, Fernando</creatorcontrib><creatorcontrib>Moreno, Felipe</creatorcontrib><creatorcontrib>Moreno-Pelayo, Miguel-Angel</creatorcontrib><creatorcontrib>Richardson, Guy P.</creatorcontrib><title>Three deaf mice: mouse models for TECTA-based human hereditary deafness reveal domain-specific structural phenotypes in the tectorial membrane</title><title>Human molecular genetics</title><addtitle>Hum Mol Genet</addtitle><description>Tecta is a modular, non-collagenous protein of the tectorial membrane (TM), an extracellular matrix of the cochlea essential for normal hearing. Missense mutations in Tecta cause dominant forms of non-syndromic deafness and a genotype–phenotype correlation has been reported in humans, with mutations in different Tecta domains causing mid- or high-frequency hearing impairments that are either stable or progressive. Three mutant mice were created as models for human Tecta mutations; the TectaL1820F,G1824D/+ mouse for zona pellucida (ZP) domain mutations causing stable mid-frequency hearing loss in a Belgian family, the TectaC1837G/+ mouse for a ZP-domain mutation underlying progressive mid-frequency hearing loss in a Spanish family and the TectaC1619S/+ mouse for a zonadhesin-like (ZA) domain mutation responsible for progressive, high-frequency hearing loss in a French family. Mutations in the ZP and ZA domains generate distinctly different changes in the structure of the TM. Auditory brainstem response thresholds in the 8–40 kHz range are elevated by 30–40 dB in the ZP-domain mutants, whilst those in the ZA-domain mutant are elevated by 20–30 dB. The phenotypes are stable and no evidence has been found for a progressive deterioration in TM structure or auditory function. Despite elevated auditory thresholds, the Tecta mutant mice all exhibit an enhanced tendency to have audiogenic seizures in response to white noise stimuli at low sound pressure levels (≤84 dB SPL), revealing a previously unrecognised consequence of Tecta mutations. These results, together with those from previous studies, establish an allelic series for Tecta unequivocally demonstrating an association between genotype and phenotype.</description><subject>Acoustic Stimulation</subject><subject>Animals</subject><subject>Deafness - genetics</subject><subject>Deafness - pathology</subject><subject>Deafness - physiopathology</subject><subject>Disease Models, Animal</subject><subject>Epilepsy, Reflex - genetics</subject><subject>Extracellular Matrix Proteins - genetics</subject><subject>Female</subject><subject>Genetic Association Studies</subject><subject>Genetic Predisposition to Disease</subject><subject>GPI-Linked Proteins - genetics</subject><subject>Hair Cells, Auditory, Inner - pathology</subject><subject>Homozygote</subject><subject>Humans</subject><subject>Male</subject><subject>Mice, 129 Strain</subject><subject>Mice, Transgenic</subject><subject>Molecular Motor Proteins - metabolism</subject><subject>Mutation, Missense</subject><subject>Organ of Corti - pathology</subject><subject>Phenotype</subject><subject>Tectorial Membrane - metabolism</subject><subject>Tectorial Membrane - pathology</subject><issn>0964-6906</issn><issn>1460-2083</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><recordid>eNqNkUFrHSEUhaW0NC9pN_0BxU0hFKbR0XHGLALhkaSFQDezF5_eyVjGcaJOIH-iv7mmLw3JJhRBF-fzcM89CH2i5Bslkp2M_ubE2iy4eIM2lAtS1aRjb9GGSMErIYk4QIcp_SKECs7a9-ig5kwwIvgG_e7HCIAt6AF7Z-AU-7AmKLeFKeEhRNxfbPvzaqcTWDyuXs94hAjWZR3v_36cISUc4Q70hG3w2s1VWsC4wRmcclxNXmORlhHmkO8XSNjNOI-AM5gcoiuaB7-LeoYP6N2gpwQfH98j1F9e9Nvv1fXPqx_b8-vKcE5zxWkDVJCa8V3bSiGMIbLWZRe2pqJraTnQSMahlUZ31nYCGhBEts0AlHN2hM72tsu682ANzLlMqJbofAmlgnbqpTK7Ud2EO8WkJLTpisHxo0EMtyukrLxLBqapZCj7U7RhvKOsFuI_UNp2Hac1K-jXPWpiSCnC8DQRJeqhalWqVvuqC_z5eYYn9F-3BfiyB8K6vGb0B75PtCM</recordid><startdate>20140515</startdate><enddate>20140515</enddate><creator>Legan, P. 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Kevin ; Goodyear, Richard J. ; Morín, Matías ; Mencia, Angeles ; Pollard, Hilary ; Olavarrieta, Leticia ; Korchagina, Julia ; Modamio-Hoybjor, Silvia ; Mayo, Fernando ; Moreno, Felipe ; Moreno-Pelayo, Miguel-Angel ; Richardson, Guy P.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c441t-415e160234b77966cc092a093d216871717e5934e79ca8dd86e5e60975fe1443</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Acoustic Stimulation</topic><topic>Animals</topic><topic>Deafness - genetics</topic><topic>Deafness - pathology</topic><topic>Deafness - physiopathology</topic><topic>Disease Models, Animal</topic><topic>Epilepsy, Reflex - genetics</topic><topic>Extracellular Matrix Proteins - genetics</topic><topic>Female</topic><topic>Genetic Association Studies</topic><topic>Genetic Predisposition to Disease</topic><topic>GPI-Linked Proteins - genetics</topic><topic>Hair Cells, Auditory, Inner - pathology</topic><topic>Homozygote</topic><topic>Humans</topic><topic>Male</topic><topic>Mice, 129 Strain</topic><topic>Mice, Transgenic</topic><topic>Molecular Motor Proteins - metabolism</topic><topic>Mutation, Missense</topic><topic>Organ of Corti - pathology</topic><topic>Phenotype</topic><topic>Tectorial Membrane - metabolism</topic><topic>Tectorial Membrane - pathology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Legan, P. Kevin</creatorcontrib><creatorcontrib>Goodyear, Richard J.</creatorcontrib><creatorcontrib>Morín, Matías</creatorcontrib><creatorcontrib>Mencia, Angeles</creatorcontrib><creatorcontrib>Pollard, Hilary</creatorcontrib><creatorcontrib>Olavarrieta, Leticia</creatorcontrib><creatorcontrib>Korchagina, Julia</creatorcontrib><creatorcontrib>Modamio-Hoybjor, Silvia</creatorcontrib><creatorcontrib>Mayo, Fernando</creatorcontrib><creatorcontrib>Moreno, Felipe</creatorcontrib><creatorcontrib>Moreno-Pelayo, Miguel-Angel</creatorcontrib><creatorcontrib>Richardson, Guy P.</creatorcontrib><collection>Open Access: Oxford University Press Open Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Human molecular genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Legan, P. Kevin</au><au>Goodyear, Richard J.</au><au>Morín, Matías</au><au>Mencia, Angeles</au><au>Pollard, Hilary</au><au>Olavarrieta, Leticia</au><au>Korchagina, Julia</au><au>Modamio-Hoybjor, Silvia</au><au>Mayo, Fernando</au><au>Moreno, Felipe</au><au>Moreno-Pelayo, Miguel-Angel</au><au>Richardson, Guy P.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Three deaf mice: mouse models for TECTA-based human hereditary deafness reveal domain-specific structural phenotypes in the tectorial membrane</atitle><jtitle>Human molecular genetics</jtitle><addtitle>Hum Mol Genet</addtitle><date>2014-05-15</date><risdate>2014</risdate><volume>23</volume><issue>10</issue><spage>2551</spage><epage>2568</epage><pages>2551-2568</pages><issn>0964-6906</issn><eissn>1460-2083</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><notes>ObjectType-Article-2</notes><notes>ObjectType-Feature-1</notes><notes>These authors contributed equally to this work.</notes><notes>Senior co-authors.</notes><abstract>Tecta is a modular, non-collagenous protein of the tectorial membrane (TM), an extracellular matrix of the cochlea essential for normal hearing. Missense mutations in Tecta cause dominant forms of non-syndromic deafness and a genotype–phenotype correlation has been reported in humans, with mutations in different Tecta domains causing mid- or high-frequency hearing impairments that are either stable or progressive. Three mutant mice were created as models for human Tecta mutations; the TectaL1820F,G1824D/+ mouse for zona pellucida (ZP) domain mutations causing stable mid-frequency hearing loss in a Belgian family, the TectaC1837G/+ mouse for a ZP-domain mutation underlying progressive mid-frequency hearing loss in a Spanish family and the TectaC1619S/+ mouse for a zonadhesin-like (ZA) domain mutation responsible for progressive, high-frequency hearing loss in a French family. Mutations in the ZP and ZA domains generate distinctly different changes in the structure of the TM. Auditory brainstem response thresholds in the 8–40 kHz range are elevated by 30–40 dB in the ZP-domain mutants, whilst those in the ZA-domain mutant are elevated by 20–30 dB. The phenotypes are stable and no evidence has been found for a progressive deterioration in TM structure or auditory function. Despite elevated auditory thresholds, the Tecta mutant mice all exhibit an enhanced tendency to have audiogenic seizures in response to white noise stimuli at low sound pressure levels (≤84 dB SPL), revealing a previously unrecognised consequence of Tecta mutations. These results, together with those from previous studies, establish an allelic series for Tecta unequivocally demonstrating an association between genotype and phenotype.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>24363064</pmid><doi>10.1093/hmg/ddt646</doi><tpages>18</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Acoustic Stimulation Animals Deafness - genetics Deafness - pathology Deafness - physiopathology Disease Models, Animal Epilepsy, Reflex - genetics Extracellular Matrix Proteins - genetics Female Genetic Association Studies Genetic Predisposition to Disease GPI-Linked Proteins - genetics Hair Cells, Auditory, Inner - pathology Homozygote Humans Male Mice, 129 Strain Mice, Transgenic Molecular Motor Proteins - metabolism Mutation, Missense Organ of Corti - pathology Phenotype Tectorial Membrane - metabolism Tectorial Membrane - pathology |
title | Three deaf mice: mouse models for TECTA-based human hereditary deafness reveal domain-specific structural phenotypes in the tectorial membrane |
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