ACTA2 – Multisystemic Smooth Muscle Dysfunction Syndrome

ACTA2 encodes α-smooth muscle actin, a key cytoskeletal component of vascular and visceral smooth muscle cells. Multisystemic smooth muscle dysfunction syndrome (MSMDS) is an autosomal dominant disorder caused by heterozygous missense variants in ACTA2, especially at Arg179, leading to global smooth muscle impairment and life-threatening vascular and visceral complications.

MSMDS presents in infancy or childhood with congenital fixed dilated pupils (congenital mydriasis), patent ductus arteriosus (HP:0001643), pulmonary arterial hypertension (HP:0002092), cystic lung disease (HP:0005948), gastrointestinal hypoperistalsis (HP:0100771), megacystis (HP:0010956; HP:0000021), and wheezing (HP:0030828) (PMID:27549731, PMID:31911919, PMID:36495950). Early genetic testing is recommended in infants with congenital mydriasis or PDA.

Genetically, the recurrent de novo variant c.536G>A (p.Arg179His) accounts for the majority of cases, with additional alleles c.535C>T (p.Arg179Cys) and rare substitutions at Asn117 (c.350A>G (p.Asn117Ser)) described in unrelated patients (PMID:31911919, PMID:32093627, PMID:39867662). Over 15 probands from multiple families have been reported, and one family exhibited segregation of a novel Asn117 change in two affected daughters and a somatic mosaic mother (2 affected relatives) (PMID:32093627).

Functional studies demonstrate that R179H actin has a 40-fold increased critical concentration for polymerization, is hypersensitive to cofilin-mediated severing, and fails to localize properly to the nucleus, impairing chromatin remodeling and smooth muscle cell differentiation in vitro and in mouse and iPSC models (PMID:27551047, PMID:36909460, PMID:38919852). Acta2SMC-R179/+ mice recapitulate cerebrovascular and aortic abnormalities.

The mechanism is a dominant-negative disruption of F-actin stability and nuclear α-SMA function rather than simple haploinsufficiency. No truncating or null alleles have been reported, supporting a missense-specific pathogenic mechanism.

Integration of genetic and experimental data supports a Definitive association between ACTA2 and MSMDS. Early molecular diagnosis enables targeted surveillance for aneurysms, cerebrovascular arteriopathy, and visceral dysfunction and guides multidisciplinary management.

Key take-home: ACTA2 sequencing should be performed in infants with congenital mydriasis or PDA to enable prompt diagnosis and tailored prevention of life-threatening vascular and visceral complications.

References

• World journal for pediatric & congenital heart surgery • 2017 • Extracorporeal Life Support in Multisystem Smooth Muscle Dysfunction Syndrome. PMID:27549731
• World journal of clinical cases • 2019 • Multisystem smooth muscle dysfunction syndrome in a Chinese girl: A case report and review of the literature. PMID:31911919
• BMC ophthalmology • 2020 • High-resolution iris and retinal imaging in multisystemic smooth muscle dysfunction syndrome due to a novel Asn117Lys substitution in ACTA2: a case report. PMID:32093627
• Urology • 2023 • Megacystis Associated With an Underlying ACTA2 Variant and Diagnosis of Multisystemic Smooth Muscle Dysfunction Syndrome: A Case Report. PMID:36495950
• The Journal of Biological Chemistry • 2016 • Severe Molecular Defects Exhibited by the R179H Mutation in Human Vascular Smooth Muscle α-Actin. PMID:27551047
• Research square • 2023 • Nuclear Smooth Muscle α-actin in Vascular Smooth Muscle Cell Differentiation. PMID:36909460
• Nature cardiovascular research • 2023 • Nuclear Smooth Muscle α-actin Participates in Vascular Smooth Muscle Cell Differentiation. PMID:38919852

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