Tbc1d32-KO Mouse

Tbc1d32, also known as BROMI, is a gene involved in the development and function of cilia. It interacts with proteins like CCRK/CDK20, CFAP20, and FAM149B1/JBTS36, contributing to the intraflagellar transport (IFT) turnaround process at the ciliary tip, which is crucial for the anterograde and retrograde trafficking of ciliary proteins. Tbc1d32 is also implicated in the Sonic Hedgehog (Shh) signaling pathway [3,4].

In humans, loss-of-function variants in Tbc1d32 have been associated with various conditions. In retinal development, Tbc1d32 expression is crucial. Its variants disrupt retinal ciliogenesis, leading to retinitis pigmentosa (RP). In iPSC-derived retinal models, Tbc1d32 mutations cause elongated ciliary defects, disrupted apical tight junctions, loss of retinoid cycling functionality, and epithelial-mesenchymal transition-like phenotypes. Photoreceptor differentiation defects, including connecting cilium anomalies, also occur, impairing trafficking to the outer segment in cones and rods [1,5]. Moreover, Tbc1d32 variants are linked to syndromic hypopituitarism, likely via disrupted Shh signaling. The gene is expressed in the developing hypothalamus, Rathke's pouch, and hindbrain areas [4]. There are also reports of Tbc1d32-associated conditions in prenatal and pediatric patients, expanding the phenotypic spectrum of a complex ciliopathy [2].

In summary, Tbc1d32 plays a vital role in cilia-related processes and in signaling pathways such as Shh. Model-based research, including human iPSC-derived models, has revealed its significance in retinal development and function, as well as in pituitary gland development. Its malfunction is associated with diseases like retinitis pigmentosa and syndromic hypopituitarism, highlighting the importance of understanding Tbc1d32 for disease diagnosis and potential treatment strategies [1,2,4,5].

References:

1. Bocquet, Béatrice, Borday, Caroline, Erkilic, Nejla, Perron, Muriel, Kalatzis, Vasiliki. 2023. TBC1D32 variants disrupt retinal ciliogenesis and cause retinitis pigmentosa. In JCI insight, 8, . doi:10.1172/jci.insight.169426. https://pubmed.ncbi.nlm.nih.gov/37768732/

2. Harris, Sarah C, Chong, Karen, Chitayat, David, Davis, Erica E, Vora, Neeta L. 2023. Diagnosis of TBC1D32-associated conditions: Expanding the phenotypic spectrum of a complex ciliopathy. In American journal of medical genetics. Part A, 191, 1282-1292. doi:10.1002/ajmg.a.63150. https://pubmed.ncbi.nlm.nih.gov/36826837/

3. Satoda, Yuuki, Noguchi, Tatsuro, Fujii, Taiju, Katoh, Yohei, Nakayama, Kazuhisa. 2022. BROMI/TBC1D32 together with CCRK/CDK20 and FAM149B1/JBTS36 contributes to intraflagellar transport turnaround involving ICK/CILK1. In Molecular biology of the cell, 33, ar79. doi:10.1091/mbc.E22-03-0089. https://pubmed.ncbi.nlm.nih.gov/35609210/

4. Hietamäki, Johanna, Gregory, Louise C, Ayoub, Sandy, Dattani, Mehul T, Raivio, Taneli. . Loss-of-Function Variants in TBC1D32 Underlie Syndromic Hypopituitarism. In The Journal of clinical endocrinology and metabolism, 105, 1748-58. doi:10.1210/clinem/dgaa078. https://pubmed.ncbi.nlm.nih.gov/32060556/

5. Sangermano, Riccardo, Place, Emily M, Pierce, Eric A, Bujakowska, Kinga M. . Novel Potentially Pathogenic Variants in TBC1D32 Cause Non-syndromic Rod-Cone Degeneration. In Advances in experimental medicine and biology, 1468, 41-44. doi:10.1007/978-3-031-76550-6_7. https://pubmed.ncbi.nlm.nih.gov/39930170/