A Novel Variant in TUBB4B Causes Progressive Cone‐Rod Dystrophy and Early Onset Sensorineural Hearing Loss
ABSTRACT Background Sensorineural hearing loss (SNHL) is a frequent manifestation of syndromic inherited retinal diseases (IRDs), exemplified by the very rare form of autosomal‐dominant Leber congenital amaurosis with early onset deafness (LCAEOD; OMIM #617879). LCAEOD was first described in 2017 in...
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Wiley
2025-02-01
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| Series: | Molecular Genetics & Genomic Medicine |
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| Online Access: | https://doi.org/10.1002/mgg3.70068 |
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| author | Margherita Scarpato Francesco Testa Anna Nesti Roberta Zeuli Rosa Boccia Gennaro Auletta Sandro Banfi Francesca Simonelli Marianthi Karali |
| author_facet | Margherita Scarpato Francesco Testa Anna Nesti Roberta Zeuli Rosa Boccia Gennaro Auletta Sandro Banfi Francesca Simonelli Marianthi Karali |
| author_sort | Margherita Scarpato |
| collection | DOAJ |
| description | ABSTRACT Background Sensorineural hearing loss (SNHL) is a frequent manifestation of syndromic inherited retinal diseases (IRDs), exemplified by the very rare form of autosomal‐dominant Leber congenital amaurosis with early onset deafness (LCAEOD; OMIM #617879). LCAEOD was first described in 2017 in four families segregating heterozygous missense mutations in TUBB4B, a gene encoding a β‐tubulin isotype. To date, only eight more families with similar TUBB4B‐associated sensorineural disease (SND) have been reported. Most cases harbored missense variants affecting the same amino acid (Arg391) and only three families segregated variants involving different residues (Tyr310, Arg390). Methods We performed whole‐exome sequencing and a full ophthalmological and audiological examination of the affected members in an Italian family segregating syndromic IRD with early onset deafness. Results We identified a novel, ultra‐rare, disease‐causing variant in TUBB4B (NM_006088.6:c.1049A>C) that replaces a highly conserved lysine with threonine at amino acid position 350. The functional impact of the Lys350Thr substitution was supported by protein structure modeling studies. The variant segregates in the family members presenting retinal disease with early onset SNHL. Detailed ophthalmological assessment of the affected subjects diagnosed a progressive cone‐rod dystrophy. Conclusion These findings expand the limited number of disease‐causing TUBB4B variants, corroborating their association with SND forms, and suggest Lys350 is an important residue for β‐tubulin function. Interestingly, our results demonstrate that TUBB4B mutations can cause cone‐dominated retinal phenotypes. |
| format | Article |
| id | doaj-art-0cc7e76dd7c7490eacc1ca9ce038b640 |
| institution | DOAJ |
| issn | 2324-9269 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Genetics & Genomic Medicine |
| spelling | doaj-art-0cc7e76dd7c7490eacc1ca9ce038b6402025-08-20T03:11:14ZengWileyMolecular Genetics & Genomic Medicine2324-92692025-02-01132n/an/a10.1002/mgg3.70068A Novel Variant in TUBB4B Causes Progressive Cone‐Rod Dystrophy and Early Onset Sensorineural Hearing LossMargherita Scarpato0Francesco Testa1Anna Nesti2Roberta Zeuli3Rosa Boccia4Gennaro Auletta5Sandro Banfi6Francesca Simonelli7Marianthi Karali8Medical Genetics, Department of Precision Medicine University of Campania ‘Luigi Vanvitelli’ Naples ItalyMultidisciplinary Department of Medical, Surgical and Dental Sciences, Eye Clinic University of Campania ‘Luigi Vanvitelli’ Naples ItalyMultidisciplinary Department of Medical, Surgical and Dental Sciences, Eye Clinic University of Campania ‘Luigi Vanvitelli’ Naples ItalyMedical Genetics, Department of Precision Medicine University of Campania ‘Luigi Vanvitelli’ Naples ItalyMultidisciplinary Department of Medical, Surgical and Dental Sciences, Eye Clinic University of Campania ‘Luigi Vanvitelli’ Naples ItalyDepartment of Neuroscience, Reproductive Science and Dentistry University of Naples Federico II Naples ItalyMedical Genetics, Department of Precision Medicine University of Campania ‘Luigi Vanvitelli’ Naples ItalyMultidisciplinary Department of Medical, Surgical and Dental Sciences, Eye Clinic University of Campania ‘Luigi Vanvitelli’ Naples ItalyMedical Genetics, Department of Precision Medicine University of Campania ‘Luigi Vanvitelli’ Naples ItalyABSTRACT Background Sensorineural hearing loss (SNHL) is a frequent manifestation of syndromic inherited retinal diseases (IRDs), exemplified by the very rare form of autosomal‐dominant Leber congenital amaurosis with early onset deafness (LCAEOD; OMIM #617879). LCAEOD was first described in 2017 in four families segregating heterozygous missense mutations in TUBB4B, a gene encoding a β‐tubulin isotype. To date, only eight more families with similar TUBB4B‐associated sensorineural disease (SND) have been reported. Most cases harbored missense variants affecting the same amino acid (Arg391) and only three families segregated variants involving different residues (Tyr310, Arg390). Methods We performed whole‐exome sequencing and a full ophthalmological and audiological examination of the affected members in an Italian family segregating syndromic IRD with early onset deafness. Results We identified a novel, ultra‐rare, disease‐causing variant in TUBB4B (NM_006088.6:c.1049A>C) that replaces a highly conserved lysine with threonine at amino acid position 350. The functional impact of the Lys350Thr substitution was supported by protein structure modeling studies. The variant segregates in the family members presenting retinal disease with early onset SNHL. Detailed ophthalmological assessment of the affected subjects diagnosed a progressive cone‐rod dystrophy. Conclusion These findings expand the limited number of disease‐causing TUBB4B variants, corroborating their association with SND forms, and suggest Lys350 is an important residue for β‐tubulin function. Interestingly, our results demonstrate that TUBB4B mutations can cause cone‐dominated retinal phenotypes.https://doi.org/10.1002/mgg3.70068progressive cone‐rod dystrophysensorineural hearing losssyndromic inherited retinal diseaseTUBB4B |
| spellingShingle | Margherita Scarpato Francesco Testa Anna Nesti Roberta Zeuli Rosa Boccia Gennaro Auletta Sandro Banfi Francesca Simonelli Marianthi Karali A Novel Variant in TUBB4B Causes Progressive Cone‐Rod Dystrophy and Early Onset Sensorineural Hearing Loss Molecular Genetics & Genomic Medicine progressive cone‐rod dystrophy sensorineural hearing loss syndromic inherited retinal disease TUBB4B |
| title | A Novel Variant in TUBB4B Causes Progressive Cone‐Rod Dystrophy and Early Onset Sensorineural Hearing Loss |
| title_full | A Novel Variant in TUBB4B Causes Progressive Cone‐Rod Dystrophy and Early Onset Sensorineural Hearing Loss |
| title_fullStr | A Novel Variant in TUBB4B Causes Progressive Cone‐Rod Dystrophy and Early Onset Sensorineural Hearing Loss |
| title_full_unstemmed | A Novel Variant in TUBB4B Causes Progressive Cone‐Rod Dystrophy and Early Onset Sensorineural Hearing Loss |
| title_short | A Novel Variant in TUBB4B Causes Progressive Cone‐Rod Dystrophy and Early Onset Sensorineural Hearing Loss |
| title_sort | novel variant in tubb4b causes progressive cone rod dystrophy and early onset sensorineural hearing loss |
| topic | progressive cone‐rod dystrophy sensorineural hearing loss syndromic inherited retinal disease TUBB4B |
| url | https://doi.org/10.1002/mgg3.70068 |
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