ACTA2 encodes actin alpha 2, smooth muscle (377 aa). Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells Highest expression in Artery Tibial (7,732 TPM) and Artery Aorta (5,736 TPM).

Multisystemic smooth muscle dysfunction syndrome is caused by mutations in the ACTA2 gene on chromosome 10.

The ACTA2 protein participates in ACTA2 gene expression is stimulated by NOTCH1, NOTCH2 and NOTCH4, Mammary myoepithelial progenitor cell produces mature myoepithelial cell, and Mammary stem cell produces myoepithelial/basal progenitor pathways.

ACTA2 is classified as a druggable target (Clinically Actionable category) with score 1.6.

56 pathogenic variants reported in ACTA2 in ClinVar, including hotspot variants 263578 and 199675.

Genetic testing for ACTA2 is available. Testing is considered confirmatory for diagnosis.

No approved treatments are currently available for multisystemic smooth muscle dysfunction syndrome. An additional 1 compound holds orphan drug designation.

Orphan Drug Designations

While no drugs are FDA-approved specifically for multisystemic smooth muscle dysfunction syndrome, some of the following designated compounds may be used off-label in clinical practice. Treatment decisions should be made in consultation with a specialist familiar with this condition.

The following drugs have received orphan drug designation from the FDA for multisystemic smooth muscle dysfunction syndrome. Orphan designation reflects regulatory interest and does not indicate approval for treatment.

Brand Name. Generic Name. Sponsor. Designated. Exclusivity End. Designation Status. a gene editing therapy that uses a CRISPR (clustered regularly interspaced short palindromic repeats)-based adenosine base editor (ABE), delivered using a smooth muscle cell targeting adeno-associated virus (AAV) capsid called AAV-PR (comprised of the parent AAV9 capsid modified with a unique 7-mer amino acid after amino acid 588 of VP1 protein). a gene editing therapy that uses a CRISPR (clustered regularly interspaced short palindromic repeats)-based adenosine base editor (ABE), delivered using a smooth muscle cell targeting adeno-associated virus (AAV) capsid called AAV-PR (comprised of the parent AAV9 capsid modified with a unique 7-mer amino acid after amino acid 588 of VP1 protein). Mass General Brigham. 2024. —. Designated

Gene therapy approaches for multisystemic smooth muscle dysfunction syndrome have been reported in the published literature.

Phenotype severity distribution: 3 always present features, 2 very common features, 7 common features.

Estimated prevalence: <1 in 1,000,000 (VERY_RARE).

2 clinical trials registered. Interventions under study include drug therapy and other interventions. Pipeline includes 1 NA. Research is primarily sponsored by academic and government institutions.

11 publications have been identified in PubMed for multisystemic smooth muscle dysfunction syndrome. Research spans Case Report / Case Series (27%), Basic Science / Preclinical (27%), and Gene Therapy / Novel Therapeutics (27%).

Recent Publications

• Rahman AA (2026). [PMID: 41493807](https://pubmed.ncbi.nlm.nih.gov/41493807/). *JCI Insight*. [Basic Science / Preclinical]

• Imai T (2026). [PMID: 41659425](https://pubmed.ncbi.nlm.nih.gov/41659425/). *bioRxiv*. [Basic Science / Preclinical]

• Alves CRR (2025). [PMID: 40935887](https://pubmed.ncbi.nlm.nih.gov/40935887/). *Nat Biomed Eng*. [Gene Therapy / Novel Therapeutics]

• Ding Q (2025). [PMID: 40378078](https://pubmed.ncbi.nlm.nih.gov/40378078/). *Circulation*. [Basic Science / Preclinical]

• Dong L (2025). [PMID: 40054993](https://pubmed.ncbi.nlm.nih.gov/40054993/). *Stroke Vasc Neurol*. [Other]

• Nakamura A (2024). [PMID: 39367156](https://pubmed.ncbi.nlm.nih.gov/39367156/). *Sci Rep*. [Gene Therapy / Novel Therapeutics]

• Alves CRR (2024). [PMID: 39605323](https://pubmed.ncbi.nlm.nih.gov/39605323/). *bioRxiv*. [Gene Therapy / Novel Therapeutics]

• Tsui JC (2024). [PMID: 37480912](https://pubmed.ncbi.nlm.nih.gov/37480912/). *Ophthalmology*. [Case Report / Case Series]

• Stanworth M (2024). [PMID: 39480826](https://pubmed.ncbi.nlm.nih.gov/39480826/). *PLoS One*. [Review / Meta-Analysis]

• Song JR (2024). [PMID: 38584446](https://pubmed.ncbi.nlm.nih.gov/38584446/). *Korean J Ophthalmol*. [Case Report / Case Series]