CC2D1A causes ciliopathy, intellectual disability, heterotaxy, renal dysplasia, and abnormal CSF flow.

Autor:	Kim AH; Department of Pediatrics, Yale School of Medicine, New Haven, CT, USA., Sakin I; Department of ENT, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.; Acibadem University School of Medicine, Istanbul, Turkey., Viviano S; Department of Pediatrics, Yale School of Medicine, New Haven, CT, USA., Tuncel G; DESAM Research Institute, Near East University, Nicosia, Cyprus., Aguilera SM; Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA., Goles G; Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA., Jeffries L; Pediatric Genomics Discovery Program, Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA., Ji W; Pediatric Genomics Discovery Program, Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA., Lakhani SA; Department of Pediatrics, Yale School of Medicine, New Haven, CT, USA.; Pediatric Genomics Discovery Program, Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA., Kose CC; Canakkale 18 March University, Faculty of Medicine, Department of Medical Genetics, Canakkale, Turkey., Silan F; Canakkale 18 March University, Faculty of Medicine, Department of Medical Genetics, Canakkale, Turkey., Oner SS; Department of Pharmacology, Goztepe Prof. Dr. Suleyman Yalcin City Hospital, Istanbul, Turkey.; Istanbul Medeniyet University, Science and Advanced Technologies Research Center (BILTAM), Istanbul, Turkey., Kaplan OI; Rare Disease Laboratory, School of Life and Natural Sciences, Abdullah Gul University, Kayseri, Turkey., Ergoren MC; Department of Medical Genetics, Faculty of Medicine, Near East University, Nicosia, Cyprus., Mishra-Gorur K; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA., Gunel M; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.; Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.; Yale Program in Brain Tumor Research, Yale University School of Medicine, New Haven, CT, USA.; Department of Neuroscience, Yale University School of Medicine, New Haven, CT, USA., Sag SO; Department of Medical Genetics, Faculty of Medicine, Uludag University, Bursa, Turkey., Temel SG; Department of Medical Genetics, Faculty of Medicine, Uludag University, Bursa, Turkey sehime@uludag.edu.tr.; Department of Histology and Embryology and Health Sciences Institute, Department of Translational Medicine, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey., Deniz E; Department of Pediatrics, Yale School of Medicine, New Haven, CT, USA engin.deniz@yale.edu.; Pediatric Genomics Discovery Program, Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA.
Jazyk:	angličtina
Zdroj:	Life science alliance [Life Sci Alliance] 2024 Aug 21; Vol. 7 (10). Date of Electronic Publication: 2024 Aug 21 (Print Publication: 2024).
DOI:	10.26508/lsa.202402708
Abstrakt:	Intellectual and developmental disabilities result from abnormal nervous system development. Over a 1,000 genes have been associated with intellectual and developmental disabilities, driving continued efforts toward dissecting variant functionality to enhance our understanding of the disease mechanism. This report identified two novel variants in CC2D1A in a cohort of four patients from two unrelated families. We used multiple model systems for functional analysis, including Xenopus , Drosophila , and patient-derived fibroblasts. Our experiments revealed that cc2d1a is expressed explicitly in a spectrum of ciliated tissues, including the left-right organizer, epidermis, pronephric duct, nephrostomes, and ventricular zone of the brain. In line with this expression pattern, loss of cc2d1a led to cardiac heterotaxy, cystic kidneys, and abnormal CSF circulation via defective ciliogenesis. Interestingly, when we analyzed brain development, mutant tadpoles showed abnormal CSF circulation only in the midbrain region, suggesting abnormal local CSF flow. Furthermore, our analysis of the patient-derived fibroblasts confirmed defective ciliogenesis, further supporting our observations. In summary, we revealed novel insight into the role of CC2D1A by establishing its new critical role in ciliogenesis and CSF circulation. (© 2024 Kim et al.)
Databáze:	MEDLINE
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