Biallelic Inactivating TUB Variants Cause Retinal Ciliopathy Impairing Biogenesis and the Structure of the Primary Cilium
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Published:2022-11-24
Issue:23
Volume:23
Page:14656
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ISSN:1422-0067
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Container-title:International Journal of Molecular Sciences
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language:en
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Short-container-title:IJMS
Author:
Ziccardi LuciaORCID,
Niceta MarcelloORCID,
Stellacci EmiliaORCID,
Ciolfi AndreaORCID,
Tatti Massimo,
Bruselles AlessandroORCID,
Mancini Cecilia,
Barbano Lucilla,
Cecchetti SerenaORCID,
Costanzo Eliana,
Cappa MarcoORCID,
Parravano Mariacristina,
Varano Monica,
Tartaglia MarcoORCID,
Cordeddu Viviana
Abstract
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.
Funder
Ministry of Health
Bietti funds
Fondazione Roma
Istituto Superiore di Sanità
Bando Ricerca Indipendente
Italian Ministry of Health
Italian Ministry of Research
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis