Gorasp1, encoding the Golgi-associated peripheral protein GRASP65, is crucial for Golgi cisternal stacking in vitro [1,2,3,4,5,6]. It is involved in pathways related to cell division, glycosylation, and vesicle-targeting mechanisms in the Golgi apparatus [1,2]. Understanding its function can be enhanced through genetic models.

In a patient with a neurodevelopmental disorder and other abnormalities, a pathogenic variant in Gorasp1 led to a total absence of GRASP65. This caused glycosylation anomalies like hyposialylation and cell-cycle delays with an excess of prometaphases and metaphases with polar chromosomes. Similar phenotypes were seen in RPE cells with a CRISPR-Cas9-introduced mutation [1]. In mice lacking both Gorasp1 (GRASP65) and Gorasp2 (GRASP55), Golgi cisternae remained stacked but were laterally disconnected, and cisternal cross-sectional diameters were reduced, suggesting a role in linking stacks and affecting COPI budding and vesicle fusion [3].

In conclusion, Gorasp1 is essential for Golgi-related functions such as cisternal stacking, glycosylation, and cell-cycle regulation. Mouse models, especially those with combined loss of Gorasp1 and Gorasp2, have provided insights into its role in maintaining Golgi structure and function, which may be relevant to understanding certain human disorders with neurodevelopmental, neurosensory, neuromuscular, and skeletal abnormalities [1,3].

References:

1. Lebon, Sophie, Bruneel, Arnaud, Drunat, Séverine, Dorboz, Imen, El Ghouzzi, Vincent. 2025. A biallelic variant in GORASP1 causes a novel Golgipathy with glycosylation and mitotic defects. In Life science alliance, 8, . doi:10.26508/lsa.202403065. https://pubmed.ncbi.nlm.nih.gov/39933924/

2. Petrosyan, Armen, Ali, Mohamed F, Cheng, Pi-Wan. 2012. Glycosyltransferase-specific Golgi-targeting mechanisms. In The Journal of biological chemistry, 287, 37621-7. doi:10.1074/jbc.C112.403006. https://pubmed.ncbi.nlm.nih.gov/22988244/

3. Grond, Rianne, Veenendaal, Tineke, Duran, Juan M, Malhotra, Vivek, Rabouille, Catherine. . The function of GORASPs in Golgi apparatus organization in vivo. In The Journal of cell biology, 219, . doi:10.1083/jcb.202004191. https://pubmed.ncbi.nlm.nih.gov/32573693/

4. Tang, Danming, Wang, Yanzhuang. 2013. Cell cycle regulation of Golgi membrane dynamics. In Trends in cell biology, 23, 296-304. doi:10.1016/j.tcb.2013.01.008. https://pubmed.ncbi.nlm.nih.gov/23453991/

5. Mahanty, Sarmistha, Bergam, Ptissam, Belapurkar, Vivek, Raposo, Graça, Setty, Subba Rao Gangi. 2024. Biogenesis of specialized lysosomes in differentiated keratinocytes relies on close apposition with the Golgi apparatus. In Cell death & disease, 15, 496. doi:10.1038/s41419-024-06710-w. https://pubmed.ncbi.nlm.nih.gov/38992005/

6. Cervigni, Romina Ines, Bonavita, Raffaella, Barretta, Maria Luisa, Corda, Daniela, Colanzi, Antonino. 2015. JNK2 controls fragmentation of the Golgi complex and the G2/M transition through phosphorylation of GRASP65. In Journal of cell science, 128, 2249-60. doi:10.1242/jcs.164871. https://pubmed.ncbi.nlm.nih.gov/25948586/