A Mutation in Synaptojanin 2 Causes Progressive Hearing Loss in the ENU-Mutagenised Mouse Strain Mozart
Identifieur interne : 000569 ( Main/Exploration ); précédent : 000568; suivant : 000570A Mutation in Synaptojanin 2 Causes Progressive Hearing Loss in the ENU-Mutagenised Mouse Strain Mozart
Auteurs : Shehnaaz S. M. Manji [Australie] ; Louise H. Williams [Australie] ; Kerry A. Miller [Australie] ; Lisa M. Ooms [Australie] ; Melanie Bahlo [Australie] ; Christina A. Mitchell [Australie] ; Hans-Henrik M. Dahl [Australie]Source :
- PLoS ONE ; 2011.
English descriptors
- KwdEn :
- Amino Acid Sequence, Amino Acid Substitution (genetics), Animals, Behavior, Animal, Ethylnitrosourea, Hair Cells, Auditory (metabolism), Hair Cells, Auditory (pathology), Hearing Loss, Sensorineural (enzymology), Hearing Loss, Sensorineural (genetics), Hearing Loss, Sensorineural (physiopathology), Male, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Molecular Sequence Data, Mutagenesis (genetics), Mutation (genetics), Nerve Fibers (metabolism), Nerve Fibers (pathology), Nerve Tissue Proteins (chemistry), Nerve Tissue Proteins (genetics), Neural Conduction (physiology), Phosphoric Monoester Hydrolases (chemistry), Phosphoric Monoester Hydrolases (genetics), Spiral Ganglion (metabolism), Spiral Ganglion (pathology), Vestibule, Labyrinth (metabolism), Vestibule, Labyrinth (pathology), Vestibule, Labyrinth (physiopathology).
- MESH :
- chemical , chemistry : Nerve Tissue Proteins, Phosphoric Monoester Hydrolases.
- chemical , genetics : Nerve Tissue Proteins, Phosphoric Monoester Hydrolases.
- chemical : Ethylnitrosourea.
- enzymology : Hearing Loss, Sensorineural.
- genetics : Amino Acid Substitution, Hearing Loss, Sensorineural, Mutagenesis, Mutation.
- metabolism : Hair Cells, Auditory, Nerve Fibers, Spiral Ganglion, Vestibule, Labyrinth.
- pathology : Hair Cells, Auditory, Nerve Fibers, Spiral Ganglion, Vestibule, Labyrinth.
- physiology : Neural Conduction.
- physiopathology : Hearing Loss, Sensorineural, Vestibule, Labyrinth.
- Amino Acid Sequence, Animals, Behavior, Animal, Male, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Molecular Sequence Data.
Abstract
Hearing impairment is the most common sensory impairment in humans, affecting 1∶1,000 births. We have identified an ENU generated mouse mutant,
The hearing loss in
Phosphoinositides are membrane associated signaling molecules that regulate many cellular processes including cell death, proliferation, actin polymerization and ion channel activity. These results reveal Synj2 as a critical regulator of hair cell survival that is essential for hair cell maintenance and hearing function.
Url:
DOI: 10.1371/journal.pone.0017607
PubMed: 21423608
PubMed Central: 3057978
Affiliations:
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Williams</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Genetic Hearing Research, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Genetic Hearing Research, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria</wicri:regionArea><wicri:noRegion>Victoria</wicri:noRegion></affiliation></author><author><name sortKey="Miller, Kerry A" sort="Miller, Kerry A" uniqKey="Miller K" first="Kerry A." last="Miller">Kerry A. 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Mitchell</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria</wicri:regionArea><wicri:noRegion>Victoria</wicri:noRegion></affiliation></author><author><name sortKey="Dahl, Hans Henrik M" sort="Dahl, Hans Henrik M" uniqKey="Dahl H" first="Hans-Henrik M." last="Dahl">Hans-Henrik M. Dahl</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Genetic Hearing Research, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Genetic Hearing Research, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria</wicri:regionArea><wicri:noRegion>Victoria</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Department of Paediatrics, Melbourne University, Royal Children's Hospital, Parkville, Victoria, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Paediatrics, Melbourne University, Royal Children's Hospital, Parkville, Victoria</wicri:regionArea><wicri:noRegion>Victoria</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">21423608</idno><idno type="pmc">3057978</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3057978</idno><idno type="RBID">PMC:3057978</idno><idno type="doi">10.1371/journal.pone.0017607</idno><date when="2011">2011</date><idno type="wicri:Area/Pmc/Corpus">000800</idno><idno type="wicri:Area/Pmc/Curation">000800</idno><idno type="wicri:Area/Pmc/Checkpoint">000353</idno><idno type="wicri:source">PubMed</idno><idno type="wicri:Area/PubMed/Corpus">000087</idno><idno type="wicri:Area/PubMed/Curation">000087</idno><idno type="wicri:Area/PubMed/Checkpoint">000085</idno><idno type="wicri:Area/Ncbi/Merge">000453</idno><idno type="wicri:Area/Ncbi/Curation">000453</idno><idno type="wicri:Area/Ncbi/Checkpoint">000453</idno><idno type="wicri:Area/Main/Merge">000571</idno><idno type="wicri:Area/Main/Curation">000569</idno><idno type="wicri:Area/Main/Exploration">000569</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">A Mutation in Synaptojanin 2 Causes Progressive Hearing Loss in the ENU-Mutagenised Mouse Strain <italic>Mozart</italic></title><author><name sortKey="Manji, Shehnaaz S M" sort="Manji, Shehnaaz S M" uniqKey="Manji S" first="Shehnaaz S. M." last="Manji">Shehnaaz S. M. Manji</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Genetic Hearing Research, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Genetic Hearing Research, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria</wicri:regionArea><wicri:noRegion>Victoria</wicri:noRegion></affiliation></author><author><name sortKey="Williams, Louise H" sort="Williams, Louise H" uniqKey="Williams L" first="Louise H." last="Williams">Louise H. Williams</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Genetic Hearing Research, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Genetic Hearing Research, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria</wicri:regionArea><wicri:noRegion>Victoria</wicri:noRegion></affiliation></author><author><name sortKey="Miller, Kerry A" sort="Miller, Kerry A" uniqKey="Miller K" first="Kerry A." last="Miller">Kerry A. Miller</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Genetic Hearing Research, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Genetic Hearing Research, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria</wicri:regionArea><wicri:noRegion>Victoria</wicri:noRegion></affiliation></author><author><name sortKey="Ooms, Lisa M" sort="Ooms, Lisa M" uniqKey="Ooms L" first="Lisa M." last="Ooms">Lisa M. Ooms</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria</wicri:regionArea><wicri:noRegion>Victoria</wicri:noRegion></affiliation></author><author><name sortKey="Bahlo, Melanie" sort="Bahlo, Melanie" uniqKey="Bahlo M" first="Melanie" last="Bahlo">Melanie Bahlo</name><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>Bioinformatics, Walter & Eliza Hall Institute, Parkville, Victoria, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Bioinformatics, Walter & Eliza Hall Institute, Parkville, Victoria</wicri:regionArea><wicri:noRegion>Victoria</wicri:noRegion></affiliation></author><author><name sortKey="Mitchell, Christina A" sort="Mitchell, Christina A" uniqKey="Mitchell C" first="Christina A." last="Mitchell">Christina A. Mitchell</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria</wicri:regionArea><wicri:noRegion>Victoria</wicri:noRegion></affiliation></author><author><name sortKey="Dahl, Hans Henrik M" sort="Dahl, Hans Henrik M" uniqKey="Dahl H" first="Hans-Henrik M." last="Dahl">Hans-Henrik M. Dahl</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Genetic Hearing Research, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Genetic Hearing Research, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria</wicri:regionArea><wicri:noRegion>Victoria</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Department of Paediatrics, Melbourne University, Royal Children's Hospital, Parkville, Victoria, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Paediatrics, Melbourne University, Royal Children's Hospital, Parkville, Victoria</wicri:regionArea><wicri:noRegion>Victoria</wicri:noRegion></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="e-ISSN">1932-6203</idno><imprint><date when="2011">2011</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amino Acid Sequence</term><term>Amino Acid Substitution (genetics)</term><term>Animals</term><term>Behavior, Animal</term><term>Ethylnitrosourea</term><term>Hair Cells, Auditory (metabolism)</term><term>Hair Cells, Auditory (pathology)</term><term>Hearing Loss, Sensorineural (enzymology)</term><term>Hearing Loss, Sensorineural (genetics)</term><term>Hearing Loss, Sensorineural (physiopathology)</term><term>Male</term><term>Mice</term><term>Mice, Inbred C57BL</term><term>Mice, Mutant Strains</term><term>Molecular Sequence Data</term><term>Mutagenesis (genetics)</term><term>Mutation (genetics)</term><term>Nerve Fibers (metabolism)</term><term>Nerve Fibers (pathology)</term><term>Nerve Tissue Proteins (chemistry)</term><term>Nerve Tissue Proteins (genetics)</term><term>Neural Conduction (physiology)</term><term>Phosphoric Monoester Hydrolases (chemistry)</term><term>Phosphoric Monoester Hydrolases (genetics)</term><term>Spiral Ganglion (metabolism)</term><term>Spiral Ganglion (pathology)</term><term>Vestibule, Labyrinth (metabolism)</term><term>Vestibule, Labyrinth (pathology)</term><term>Vestibule, Labyrinth (physiopathology)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Nerve Tissue Proteins</term><term>Phosphoric Monoester Hydrolases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Nerve Tissue Proteins</term><term>Phosphoric Monoester Hydrolases</term></keywords><keywords scheme="MESH" type="chemical" xml:lang="en"><term>Ethylnitrosourea</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Hearing Loss, Sensorineural</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Amino Acid Substitution</term><term>Hearing Loss, Sensorineural</term><term>Mutagenesis</term><term>Mutation</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Hair Cells, Auditory</term><term>Nerve Fibers</term><term>Spiral Ganglion</term><term>Vestibule, Labyrinth</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Hair Cells, Auditory</term><term>Nerve Fibers</term><term>Spiral Ganglion</term><term>Vestibule, Labyrinth</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Neural Conduction</term></keywords><keywords scheme="MESH" qualifier="physiopathology" xml:lang="en"><term>Hearing Loss, Sensorineural</term><term>Vestibule, Labyrinth</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Amino Acid Sequence</term><term>Animals</term><term>Behavior, Animal</term><term>Male</term><term>Mice</term><term>Mice, Inbred C57BL</term><term>Mice, Mutant Strains</term><term>Molecular Sequence Data</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p>Hearing impairment is the most common sensory impairment in humans, affecting 1∶1,000 births. We have identified an ENU generated mouse mutant, <italic>Mozart</italic>, with recessively inherited, non-syndromic progressive hearing loss caused by a mutation in the synaptojanin 2 (Synj2), a central regulatory enzyme in the phosphoinositide-signaling cascade.</p></sec><sec><title>Methodology/Principal Findings</title><p>The hearing loss in <italic>Mozart</italic> is caused by a p.Asn538Lys mutation in the catalytic domain of the inositol polyphosphate 5-phosphatase synaptojanin 2. Within the cochlea, <italic>Synj2</italic> mRNA expression was detected in the inner and outer hair cells but not in the spiral ganglion. <italic>Synj2</italic><sup>N538K</sup> mutant protein showed loss of lipid phosphatase activity, and was unable to degrade phosphoinositide signaling molecules. Mutant <italic>Mozart</italic> mice (<italic>Synj2</italic><sup>N538K/N538K</sup>) exhibited progressive hearing loss and showed signs of hair cell degeneration as early as two weeks of age, with fusion of stereocilia followed by complete loss of hair bundles and ultimately loss of hair cells. No changes in vestibular or neurological function, or other clinical or behavioral manifestations were apparent.</p></sec><sec><title>Conclusions/Significance</title><p>Phosphoinositides are membrane associated signaling molecules that regulate many cellular processes including cell death, proliferation, actin polymerization and ion channel activity. These results reveal Synj2 as a critical regulator of hair cell survival that is essential for hair cell maintenance and hearing function.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Petit, C" uniqKey="Petit C">C Petit</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Morton, Ne" uniqKey="Morton N">NE Morton</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Astle, Mv" uniqKey="Astle M">MV Astle</name></author><author><name sortKey="Seaton, G" uniqKey="Seaton G">G Seaton</name></author><author><name sortKey="Davies, Em" uniqKey="Davies E">EM Davies</name></author><author><name sortKey="Fedele, Cg" uniqKey="Fedele C">CG Fedele</name></author><author><name sortKey="Rahman, P" uniqKey="Rahman P">P Rahman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Simonsen, A" uniqKey="Simonsen A">A 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sortKey="Manji, Shehnaaz S M" sort="Manji, Shehnaaz S M" uniqKey="Manji S" first="Shehnaaz S. M." last="Manji">Shehnaaz S. M. Manji</name></noRegion><name sortKey="Bahlo, Melanie" sort="Bahlo, Melanie" uniqKey="Bahlo M" first="Melanie" last="Bahlo">Melanie Bahlo</name><name sortKey="Dahl, Hans Henrik M" sort="Dahl, Hans Henrik M" uniqKey="Dahl H" first="Hans-Henrik M." last="Dahl">Hans-Henrik M. Dahl</name><name sortKey="Dahl, Hans Henrik M" sort="Dahl, Hans Henrik M" uniqKey="Dahl H" first="Hans-Henrik M." last="Dahl">Hans-Henrik M. Dahl</name><name sortKey="Miller, Kerry A" sort="Miller, Kerry A" uniqKey="Miller K" first="Kerry A." last="Miller">Kerry A. Miller</name><name sortKey="Mitchell, Christina A" sort="Mitchell, Christina A" uniqKey="Mitchell C" first="Christina A." last="Mitchell">Christina A. Mitchell</name><name sortKey="Ooms, Lisa M" sort="Ooms, Lisa M" uniqKey="Ooms L" first="Lisa M." last="Ooms">Lisa M. Ooms</name><name sortKey="Williams, Louise H" sort="Williams, Louise H" uniqKey="Williams L" first="Louise H." last="Williams">Louise H. 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