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Biallelic Inactivating TUB Variants Cause Retinal Ciliopathy Impairing Biogenesis and the Structure of the Primary Cilium

Inherited retinal degeneration (IRD) represents a clinically variable and genetically heterogeneous group of disorders characterized by photoreceptor dysfunction. These diseases typically present with progressive severe vision loss and variable onset, ranging from birth to adulthood. Genomic sequenc...

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Autores principales: Ziccardi, Lucia, Niceta, Marcello, Stellacci, Emilia, Ciolfi, Andrea, Tatti, Massimo, Bruselles, Alessandro, Mancini, Cecilia, Barbano, Lucilla, Cecchetti, Serena, Costanzo, Eliana, Cappa, Marco, Parravano, Mariacristina, Varano, Monica, Tartaglia, Marco, Cordeddu, Viviana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9740599/
https://www.ncbi.nlm.nih.gov/pubmed/36498982
http://dx.doi.org/10.3390/ijms232314656
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author Ziccardi, Lucia
Niceta, Marcello
Stellacci, Emilia
Ciolfi, Andrea
Tatti, Massimo
Bruselles, Alessandro
Mancini, Cecilia
Barbano, Lucilla
Cecchetti, Serena
Costanzo, Eliana
Cappa, Marco
Parravano, Mariacristina
Varano, Monica
Tartaglia, Marco
Cordeddu, Viviana
author_facet Ziccardi, Lucia
Niceta, Marcello
Stellacci, Emilia
Ciolfi, Andrea
Tatti, Massimo
Bruselles, Alessandro
Mancini, Cecilia
Barbano, Lucilla
Cecchetti, Serena
Costanzo, Eliana
Cappa, Marco
Parravano, Mariacristina
Varano, Monica
Tartaglia, Marco
Cordeddu, Viviana
author_sort Ziccardi, Lucia
collection PubMed
description Inherited retinal degeneration (IRD) represents a clinically variable and genetically heterogeneous group of disorders characterized by photoreceptor dysfunction. These diseases typically present with progressive severe vision loss and variable onset, ranging from birth to adulthood. Genomic sequencing has allowed to identify novel IRD-related genes, most of which encode proteins contributing to photoreceptor-cilia biogenesis and/or function. Despite these insights, knowledge gaps hamper a molecular diagnosis in one-third of IRD cases. By exome sequencing in a cohort of molecularly unsolved individuals with IRD, we identified a homozygous splice site variant affecting the transcript processing of TUB, encoding the first member of the Tubby family of bipartite transcription factors, in a sporadic case with retinal dystrophy. A truncating homozygous variant in this gene had previously been reported in a single family with three subjects sharing retinal dystrophy and obesity. The clinical assessment of the present patient documented a slightly increased body mass index and no changes in metabolic markers of obesity, but confirmed the occurrence of retinal detachment. In vitro studies using patient-derived fibroblasts showed the accelerated degradation of the encoded protein and aberrant cilium morphology and biogenesis. These findings definitely link impaired TUB function to retinal dystrophy and provide new data on the clinical characterization of this ultra-rare retinal ciliopathy.
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spelling pubmed-97405992022-12-11 Biallelic Inactivating TUB Variants Cause Retinal Ciliopathy Impairing Biogenesis and the Structure of the Primary Cilium Ziccardi, Lucia Niceta, Marcello Stellacci, Emilia Ciolfi, Andrea Tatti, Massimo Bruselles, Alessandro Mancini, Cecilia Barbano, Lucilla Cecchetti, Serena Costanzo, Eliana Cappa, Marco Parravano, Mariacristina Varano, Monica Tartaglia, Marco Cordeddu, Viviana Int J Mol Sci Case Report Inherited retinal degeneration (IRD) represents a clinically variable and genetically heterogeneous group of disorders characterized by photoreceptor dysfunction. These diseases typically present with progressive severe vision loss and variable onset, ranging from birth to adulthood. Genomic sequencing has allowed to identify novel IRD-related genes, most of which encode proteins contributing to photoreceptor-cilia biogenesis and/or function. Despite these insights, knowledge gaps hamper a molecular diagnosis in one-third of IRD cases. By exome sequencing in a cohort of molecularly unsolved individuals with IRD, we identified a homozygous splice site variant affecting the transcript processing of TUB, encoding the first member of the Tubby family of bipartite transcription factors, in a sporadic case with retinal dystrophy. A truncating homozygous variant in this gene had previously been reported in a single family with three subjects sharing retinal dystrophy and obesity. The clinical assessment of the present patient documented a slightly increased body mass index and no changes in metabolic markers of obesity, but confirmed the occurrence of retinal detachment. In vitro studies using patient-derived fibroblasts showed the accelerated degradation of the encoded protein and aberrant cilium morphology and biogenesis. These findings definitely link impaired TUB function to retinal dystrophy and provide new data on the clinical characterization of this ultra-rare retinal ciliopathy. MDPI 2022-11-24 /pmc/articles/PMC9740599/ /pubmed/36498982 http://dx.doi.org/10.3390/ijms232314656 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Case Report
Ziccardi, Lucia
Niceta, Marcello
Stellacci, Emilia
Ciolfi, Andrea
Tatti, Massimo
Bruselles, Alessandro
Mancini, Cecilia
Barbano, Lucilla
Cecchetti, Serena
Costanzo, Eliana
Cappa, Marco
Parravano, Mariacristina
Varano, Monica
Tartaglia, Marco
Cordeddu, Viviana
Biallelic Inactivating TUB Variants Cause Retinal Ciliopathy Impairing Biogenesis and the Structure of the Primary Cilium
title Biallelic Inactivating TUB Variants Cause Retinal Ciliopathy Impairing Biogenesis and the Structure of the Primary Cilium
title_full Biallelic Inactivating TUB Variants Cause Retinal Ciliopathy Impairing Biogenesis and the Structure of the Primary Cilium
title_fullStr Biallelic Inactivating TUB Variants Cause Retinal Ciliopathy Impairing Biogenesis and the Structure of the Primary Cilium
title_full_unstemmed Biallelic Inactivating TUB Variants Cause Retinal Ciliopathy Impairing Biogenesis and the Structure of the Primary Cilium
title_short Biallelic Inactivating TUB Variants Cause Retinal Ciliopathy Impairing Biogenesis and the Structure of the Primary Cilium
title_sort biallelic inactivating tub variants cause retinal ciliopathy impairing biogenesis and the structure of the primary cilium
topic Case Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9740599/
https://www.ncbi.nlm.nih.gov/pubmed/36498982
http://dx.doi.org/10.3390/ijms232314656
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