Acta2, encoding α-smooth muscle actin, is an isoform of vascular smooth muscle actins. It is typically expressed in vascular smooth muscle cells, contributing to vascular motility and contraction [6]. Mutations in Acta2 are associated with various diffuse vasculopathies, involving pathways related to smooth muscle function and arterial integrity [6].

Missense mutations in Acta2 cause diffuse smooth muscle dysfunction and a distinct cerebral arteriopathy, known as multisystemic smooth muscle dysfunction syndrome (MSMDS) [1]. This arteriopathy is characterized by aberrant internal carotid circulation, with dilatation of proximal segments, occlusive disease at distal segments, and dolichoectasia, predisposing patients, especially children, to ischemic strokes [1]. Acta2-related diseases also include an increased susceptibility to aneurismal dilatations and dissections, patent ductus arteriosus, early-onset coronary artery disease, congenital mydriasis, chronic interstitial lung disease, hypoperistalsis, hydrops of gall bladder, and hypotonic bladder [2]. Pathogenic variants in Acta2 are also associated with brain malformations like dysgyria, with a peri-Sylvian and frontal predominance [4]. In gastric cancer, increasing tumor Acta2 expression is associated with worse overall survival and lower response to immune checkpoint inhibitors [3].

In conclusion, Acta2 is crucial for vascular smooth muscle function and its mutations lead to a wide range of diseases, mainly affecting the vascular system and other smooth-muscle-dependent organs. Research on Acta2-related diseases, through case reports and genetic analysis, helps in understanding the molecular pathogenesis and is critical for surveillance and management of associated complications [2,5].

References:

1. Cuoco, Joshua A, Busch, Christopher M, Klein, Brendan J, Nicholson, Andrew D, Marvin, Eric A. 2018. ACTA2 Cerebral Arteriopathy: Not Just a Puff of Smoke. In Cerebrovascular diseases (Basel, Switzerland), 46, 161-171. doi:10.1159/000493863. https://pubmed.ncbi.nlm.nih.gov/30300893/

2. Lupo, Viviana, Di Gregorio, Maria Grazia, Mastrogiorgio, Gerarda, Haass, Cristina, Novelli, Antonio. 2023. Neonatal diagnosis of ACTA2-related disease: A case report and review of literature. In American journal of medical genetics. Part A, 191, 1111-1118. doi:10.1002/ajmg.a.63118. https://pubmed.ncbi.nlm.nih.gov/36607831/

3. Park, Sunho, Karalis, John D, Hong, Changjin, Cheong, Jae-Ho, Hwang, Tae Hyun. . ACTA2 Expression Predicts Survival and Is Associated with Response to Immune Checkpoint Inhibitors in Gastric Cancer. In Clinical cancer research : an official journal of the American Association for Cancer Research, 29, 1077-1085. doi:10.1158/1078-0432.CCR-22-1897. https://pubmed.ncbi.nlm.nih.gov/36508166/

4. Subramanian, S, Biswas, A, Alves, C A P F, Dobyns, W B, Mankad, K. 2021. ACTA2-Related Dysgyria: An Under-Recognized Malformation of Cortical Development. In AJNR. American journal of neuroradiology, 43, 146-150. doi:10.3174/ajnr.A7364. https://pubmed.ncbi.nlm.nih.gov/34857515/

5. Kaw, Anita, Kaw, Kaveeta, Hostetler, Ellen M, Kwartler, Callie S, Milewicz, Dianna M. 2022. Expanding ACTA2 genotypes with corresponding phenotypes overlapping with smooth muscle dysfunction syndrome. In American journal of medical genetics. Part A, 188, 2389-2396. doi:10.1002/ajmg.a.62775. https://pubmed.ncbi.nlm.nih.gov/35567597/

6. Yuan, Shi-Min. . α-Smooth Muscle Actin and ACTA2 Gene Expressions in Vasculopathies. In Brazilian journal of cardiovascular surgery, 30, 644-9. doi:10.5935/1678-9741.20150081. https://pubmed.ncbi.nlm.nih.gov/26934405/