Ica1l, which has sequence similarities to ICA69 (also known as ICA1), is a gene with diverse functions. It forms BAR-domain complexes with PICK1. This interaction is crucial for acrosome formation during spermiogenesis, as it is highly expressed in spermatids and trafficked with PICK1 at different stages of this process [3].

In disease-related studies, Ica1l has been associated with several conditions. Transcriptome-wide association study (TWAS) identified an association between the expression of Ica1l and lacunar stroke [1]. Integrative analysis of proteome and transcriptome data also revealed Ica1l's association with small-vessel stroke (SVS) based on brain-derived data at both protein and transcriptional levels [2]. A proteome-wide association study (PWAS) indicated that Ica1l is associated with SVS and non-lobar intracerebral haemorrhage (ICH), and its protein levels in the brain are cis-regulated [4]. In addition, novel SRF-ICA1L fusions were found in cellular myoid neoplasms with potential for malignant behavior [5]. Mendelian randomization analysis suggested that while ICA1L might provide protection against both autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), it was also associated with these disorders at the genetic level [6]. ICA1L was also identified as a potential causal gene for migraine [8], and its protein abundance in the brain was found to be causal in Alzheimer's disease, though it was not recommended as a prioritized drug due to potential side effects [7,9].

In conclusion, Ica1l is essential for acrosome formation in spermiogenesis. Its associations with various diseases such as stroke, intracerebral haemorrhage, myoid neoplasms, ADHD, ASD, migraine, and Alzheimer's disease, as revealed through genetic and integrative omics studies, highlight its significance in understanding disease mechanisms. These findings from different research models contribute to a better understanding of the role of Ica1l in both normal biological processes and disease conditions.

References:

1. Traylor, Matthew, Persyn, Elodie, Tomppo, Liisa, Lewis, Cathryn M, Markus, Hugh S. 2021. Genetic basis of lacunar stroke: a pooled analysis of individual patient data and genome-wide association studies. In The Lancet. Neurology, 20, 351-361. doi:10.1016/S1474-4422(21)00031-4. https://pubmed.ncbi.nlm.nih.gov/33773637/

2. Wu, Bang-Sheng, Chen, Shu-Fen, Huang, Shu-Yi, Dong, Qiang, Yu, Jin-Tai. 2022. Identifying causal genes for stroke via integrating the proteome and transcriptome from brain and blood. In Journal of translational medicine, 20, 181. doi:10.1186/s12967-022-03377-9. https://pubmed.ncbi.nlm.nih.gov/35449099/

3. He, Jing, Xia, Mengying, Tsang, Wai Hung, Chow, King Lau, Xia, Jun. 2015. ICA1L forms BAR-domain complexes with PICK1 and is crucial for acrosome formation in spermiogenesis. In Journal of cell science, 128, 3822-36. doi:10.1242/jcs.173534. https://pubmed.ncbi.nlm.nih.gov/26306493/

4. Cullell, Natalia, Gallego-Fábrega, Cristina, Cárcel-Márquez, Jara, Fernández-Cadenas, Israel, Krupinski, Jerzy. 2022. ICA1L Is Associated with Small Vessel Disease: A Proteome-Wide Association Study in Small Vessel Stroke and Intracerebral Haemorrhage. In International journal of molecular sciences, 23, . doi:10.3390/ijms23063161. https://pubmed.ncbi.nlm.nih.gov/35328582/

5. Suurmeijer, Albert J, Dickson, Brendan C, Swanson, David, Zhang, Lei, Antonescu, Cristina R. . Novel SRF-ICA1L Fusions in Cellular Myoid Neoplasms With Potential For Malignant Behavior. In The American journal of surgical pathology, 44, 55-60. doi:10.1097/PAS.0000000000001336. https://pubmed.ncbi.nlm.nih.gov/31478943/

6. Zhang, Chengcheng, Jian, Lingqi, Li, Xiaojing, Hu, Xun, Li, Tao. 2024. Mendelian randomization analysis of the brain, cerebrospinal fluid, and plasma proteome identifies potential drug targets for attention deficit hyperactivity disorder. In EBioMedicine, 105, 105197. doi:10.1016/j.ebiom.2024.105197. https://pubmed.ncbi.nlm.nih.gov/38876042/

7. Ge, Yi-Jun, Ou, Ya-Nan, Deng, Yue-Ting, Tan, Lan, Yu, Jin-Tai. 2022. Prioritization of Drug Targets for Neurodegenerative Diseases by Integrating Genetic and Proteomic Data From Brain and Blood. In Biological psychiatry, 93, 770-779. doi:10.1016/j.biopsych.2022.11.002. https://pubmed.ncbi.nlm.nih.gov/36759259/

8. Li, Shuang-Jie, Shi, Jing-Jing, Mao, Cheng-Yuan, Wang, Yong-Gang, Shi, Chang-He. 2023. Identifying causal genes for migraine by integrating the proteome and transcriptome. In The journal of headache and pain, 24, 111. doi:10.1186/s10194-023-01649-3. https://pubmed.ncbi.nlm.nih.gov/37592229/

9. Ou, Ya-Nan, Yang, Yu-Xiang, Deng, Yue-Ting, Tan, Lan, Yu, Jin-Tai. 2021. Identification of novel drug targets for Alzheimer's disease by integrating genetics and proteomes from brain and blood. In Molecular psychiatry, 26, 6065-6073. doi:10.1038/s41380-021-01251-6. https://pubmed.ncbi.nlm.nih.gov/34381170/