A Novel Variant in the TBC1D24 Lipid-Binding Pocket Causes Autosomal Dominant Hearing Loss: Evidence for a Genotype-Phenotype Correlation
Background: Hereditary hearing loss is a disorder with high genetic and allelic heterogeneity. Diagnostic screening of candidate genes commonly yields novel variants of unknown clinical significance. TBC1D24 is a pleiotropic gene associated with recessive DOORS syndrome, epileptic encephalopathy, my...
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| Format: | Article |
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Frontiers Media S.A.
2020-11-01
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| Series: | Frontiers in Cellular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fncel.2020.585669/full |
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| author | Thomas Parzefall Alexandra Frohne Alexandra Frohne Martin Koenighofer Juergen Neesen Franco Laccone Julia Eckl-Dorna Jonathan J. Waters Markus Schreiner Sami Samir Amr Sami Samir Amr Emma Ashton Christian Schoefer Wolfgang Gstœttner Klemens Frei Trevor Lucas |
| author_facet | Thomas Parzefall Alexandra Frohne Alexandra Frohne Martin Koenighofer Juergen Neesen Franco Laccone Julia Eckl-Dorna Jonathan J. Waters Markus Schreiner Sami Samir Amr Sami Samir Amr Emma Ashton Christian Schoefer Wolfgang Gstœttner Klemens Frei Trevor Lucas |
| author_sort | Thomas Parzefall |
| collection | DOAJ |
| description | Background: Hereditary hearing loss is a disorder with high genetic and allelic heterogeneity. Diagnostic screening of candidate genes commonly yields novel variants of unknown clinical significance. TBC1D24 is a pleiotropic gene associated with recessive DOORS syndrome, epileptic encephalopathy, myoclonic epilepsy, and both recessive and dominant hearing impairment. Genotype-phenotype correlations have not been established to date but could facilitate diagnostic variant assessment and elucidation of pathomechanisms.Methods and Results: Whole-exome and gene panel screening identified a novel (c.919A>C; p.Asn307His) causative variant in TBC1D24 in two unrelated Caucasian families with Autosomal dominant (AD) nonsyndromic late-onset hearing loss. Protein modeling on the Drosophila TBC1D24 ortholog Skywalker crystal structure showed close interhelix proximity (6.8Å) between the highly conserved residue p.Asn307 in α18 and the position of the single known pathogenic dominant variation (p.Ser178Leu) in α11 that causes a form of deafness with similar clinical characteristics.Conclusion: Genetic variants affecting two polar hydrophilic residues in neighboring helices of TBC1D24 cause AD nonsyndromic late-onset hearing loss. The spatial proximity of the affected residues suggests the first genotype-phenotype association in TBC1D24-related disorders. Three conserved residues in α18 contribute to the formation of a functionally relevant cationic phosphoinositide binding pocket that regulates synaptic vesicle trafficking which may be involved in the molecular mechanism of disease. |
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| id | doaj.art-16015d4b45144763b1c1e2ac0e3f6326 |
| institution | Directory Open Access Journal |
| issn | 1662-5102 |
| language | English |
| last_indexed | 2024-12-14T09:17:35Z |
| publishDate | 2020-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular Neuroscience |
| spelling | doaj.art-16015d4b45144763b1c1e2ac0e3f63262022-12-21T23:08:24ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022020-11-011410.3389/fncel.2020.585669585669A Novel Variant in the TBC1D24 Lipid-Binding Pocket Causes Autosomal Dominant Hearing Loss: Evidence for a Genotype-Phenotype CorrelationThomas Parzefall0Alexandra Frohne1Alexandra Frohne2Martin Koenighofer3Juergen Neesen4Franco Laccone5Julia Eckl-Dorna6Jonathan J. Waters7Markus Schreiner8Sami Samir Amr9Sami Samir Amr10Emma Ashton11Christian Schoefer12Wolfgang Gstœttner13Klemens Frei14Trevor Lucas15Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, AustriaDepartment of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, AustriaDepartment for Cell and Developmental Biology, Orphan Disease Genetics Group, Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, AustriaDepartment of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, AustriaInstitute of Medical Genetics, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Vienna, AustriaInstitute of Medical Genetics, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Vienna, AustriaDepartment of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, AustriaRare and Inherited Disease Laboratory, London North Genomic Laboratory Hub, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United KingdomDepartment of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, AustriaLaboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, MA, United StatesDepartment of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United StatesRare and Inherited Disease Laboratory, London North Genomic Laboratory Hub, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United KingdomDepartment for Cell and Developmental Biology, Orphan Disease Genetics Group, Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, AustriaDepartment of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, AustriaDepartment of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, AustriaDepartment for Cell and Developmental Biology, Orphan Disease Genetics Group, Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, AustriaBackground: Hereditary hearing loss is a disorder with high genetic and allelic heterogeneity. Diagnostic screening of candidate genes commonly yields novel variants of unknown clinical significance. TBC1D24 is a pleiotropic gene associated with recessive DOORS syndrome, epileptic encephalopathy, myoclonic epilepsy, and both recessive and dominant hearing impairment. Genotype-phenotype correlations have not been established to date but could facilitate diagnostic variant assessment and elucidation of pathomechanisms.Methods and Results: Whole-exome and gene panel screening identified a novel (c.919A>C; p.Asn307His) causative variant in TBC1D24 in two unrelated Caucasian families with Autosomal dominant (AD) nonsyndromic late-onset hearing loss. Protein modeling on the Drosophila TBC1D24 ortholog Skywalker crystal structure showed close interhelix proximity (6.8Å) between the highly conserved residue p.Asn307 in α18 and the position of the single known pathogenic dominant variation (p.Ser178Leu) in α11 that causes a form of deafness with similar clinical characteristics.Conclusion: Genetic variants affecting two polar hydrophilic residues in neighboring helices of TBC1D24 cause AD nonsyndromic late-onset hearing loss. The spatial proximity of the affected residues suggests the first genotype-phenotype association in TBC1D24-related disorders. Three conserved residues in α18 contribute to the formation of a functionally relevant cationic phosphoinositide binding pocket that regulates synaptic vesicle trafficking which may be involved in the molecular mechanism of disease.https://www.frontiersin.org/articles/10.3389/fncel.2020.585669/fullTBC1D24DFNA65genotype-phenotype associationexome sequencingautosomal dominantnonsyndromic |
| spellingShingle | Thomas Parzefall Alexandra Frohne Alexandra Frohne Martin Koenighofer Juergen Neesen Franco Laccone Julia Eckl-Dorna Jonathan J. Waters Markus Schreiner Sami Samir Amr Sami Samir Amr Emma Ashton Christian Schoefer Wolfgang Gstœttner Klemens Frei Trevor Lucas A Novel Variant in the TBC1D24 Lipid-Binding Pocket Causes Autosomal Dominant Hearing Loss: Evidence for a Genotype-Phenotype Correlation Frontiers in Cellular Neuroscience TBC1D24 DFNA65 genotype-phenotype association exome sequencing autosomal dominant nonsyndromic |
| title | A Novel Variant in the TBC1D24 Lipid-Binding Pocket Causes Autosomal Dominant Hearing Loss: Evidence for a Genotype-Phenotype Correlation |
| title_full | A Novel Variant in the TBC1D24 Lipid-Binding Pocket Causes Autosomal Dominant Hearing Loss: Evidence for a Genotype-Phenotype Correlation |
| title_fullStr | A Novel Variant in the TBC1D24 Lipid-Binding Pocket Causes Autosomal Dominant Hearing Loss: Evidence for a Genotype-Phenotype Correlation |
| title_full_unstemmed | A Novel Variant in the TBC1D24 Lipid-Binding Pocket Causes Autosomal Dominant Hearing Loss: Evidence for a Genotype-Phenotype Correlation |
| title_short | A Novel Variant in the TBC1D24 Lipid-Binding Pocket Causes Autosomal Dominant Hearing Loss: Evidence for a Genotype-Phenotype Correlation |
| title_sort | novel variant in the tbc1d24 lipid binding pocket causes autosomal dominant hearing loss evidence for a genotype phenotype correlation |
| topic | TBC1D24 DFNA65 genotype-phenotype association exome sequencing autosomal dominant nonsyndromic |
| url | https://www.frontiersin.org/articles/10.3389/fncel.2020.585669/full |
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