CC2D1A causes ciliopathy, intellectual disability, heterotaxy, renal dysplasia, and abnormal CSF flow
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 <i>CC2D1A</i> in a cohort of four patients from two unrelated families. We used multiple model systems for functional analysis, including <i>Xenopus</i>, <i>Drosophila</i>, and patient-derived fibroblasts. Our experiments revealed that <i>cc2d1a</i> 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 <i>cc2d1a</i> 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 <i>local</i> 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 <i>CC2D1A</i> by establishing its new critical role in ciliogenesis and CSF circulation.
Authors
- Engin Deniz (ORCID: https://orcid.org/0000-0002-2999-0429)
- Murat Günel (ORCID: https://orcid.org/0000-0002-2290-7055)
- A. Kim
- Stephen Viviano (ORCID: https://orcid.org/0000-0003-2059-4531)
- Şükrü Sadik Öner (ORCID: https://orcid.org/0000-0002-8864-7356)
- Şebnem Özemri Sağ (ORCID: https://orcid.org/0000-0002-3948-8889)
- Gizem Goles (ORCID: https://orcid.org/0000-0001-7990-4878)
- Oktay I. Kaplan (ORCID: https://orcid.org/0000-0002-8733-0920)
- Gülten Tuncel (ORCID: https://orcid.org/0000-0002-3332-471X)
- Ketu Mishra-Gorur (ORCID: https://orcid.org/0000-0002-3182-4411)
- Mahmut Çerkez Ergören (ORCID: https://orcid.org/0000-0001-9593-9325)
- Şehime Gülsün Temel (ORCID: https://orcid.org/0000-0002-9802-0880)
- Weizhen Ji
- Irmak Sakin (ORCID: https://orcid.org/0000-0001-7474-4334)
- Stephanie Marie Aguilera (ORCID: https://orcid.org/0000-0001-8926-2311)
- Saquib A. Lakhani (ORCID: https://orcid.org/0000-0003-3235-3460)
- Lauren Jeffries (ORCID: https://orcid.org/0000-0002-6419-0515)
- Fatma Sılan (ORCID: https://orcid.org/0000-0001-7191-2240)
- Canan Ceylan Köse (ORCID: https://orcid.org/0000-0003-3789-2607)
Institutions
- Bursa Uludağ Üni̇versi̇tesi̇ (TR)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- Acıbadem University (TR)
- Yale University (US)
- University of New Haven (US)
- Canakkale Onsekiz Mart Universitesi Tip Fakultesi Hastanesi (TR)
- Göztepe Şafak Hastanesi (TR)
- Istanbul Medeniyet University (TR)
- Near East University (CY)
- Abdullah Gül University (TR)
Publication Details
- Journal
- Life Science Alliance
- Published
- 2024-08-21
- DOI
- https://doi.org/10.26508/lsa.202402708
- Citations
- 5
- Primary Topic
- Genetic and Kidney Cyst Diseases
- Type
- article
- Field-Weighted Citation Impact
- 2.75
Funders
- Yale University
- National Institutes of Health
- Eunice Kennedy Shriver National Institute of Child Health and Human Development