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Rare Smooth Muscle Disorder Traced to a Single Mutation in a Non-coding Gene

Key findings

  • Multisystemic smooth muscle dysfunction syndrome (MSMDS) is an extremely rare smooth muscle disease normally caused by recurrent missense variations in the gene ACTA2 that alter arginine 179
  • Through the Undiagnosed Diseases Network, a patient was referred to Massachusetts General Hospital who had signs and symptoms of MSMDS but no variant in ACTA2
  • The Mass General team detected a single-nucleotide variant in the gene MIR145, which is enriched in tissues with high smooth muscle cell content; specifically, the variant was in microRNA at nucleotide 3 of miR-145-5p
  • Transfection of small interfering RNA against mutant miR-145-5p induced substantial reduction of the expression of several cytoskeletal proteins, including transgelin, calponin, and a-smooth muscle actin; ACTA2 mutations also reduce the latter
  • It's possible additional loci are associated with MSMDS, and this case shows the potential of genetic testing for rare diseases that searches beyond protein-coding genes

Multisystemic smooth muscle dysfunction syndrome (MSMDS), an ultrarare smooth muscle myopathy, is known to be caused by recurrent missense variations in ACTA2 that alter arginine 179. These variants impair the function of α-smooth muscle actin (α-SMA).

Now, Massachusetts General Hospital researchers have described a patient whose MSMDS is associated with a single-nucleotide variant in MIR145—the first case of a monogenetic vascular disease caused by a mutation in a non–protein-encoding gene.

Christian Lacks Lino Cardenas, PhD, PharmD, instructor in Medicine at the Mass General Research Institute, Lauren C. Briere, MS, in the division of genetics at Mass General, Mark Lindsay, MD, PhD, cardiologist, and Patricia L. Musolino, MD, PhD, critical care and vascular neurologist in the Department of Neurology and co-director of the Pediatric Stroke and Cerebrovascular Program, and colleagues report the case in a letter to the editor of The Journal of Clinical Investigation.

Case Presentation

The patient's home medical team referred him to the Undiagnosed Diseases Network study sponsored by the National Institutes of Health, which comprises 12 sites, including Harvard Medical School.

The patient's history included profound gastrointestinal dysmotility, identified during infancy, and cerebrovascular disease that began with the frontal cortex and watershed strokes at approximately 2.5 years of age. Straightening of cerebral arteries and flattening of the genu of the corpus callosum and pons was observed.

During his school years, the patient had multiple strokes consistent with arterial ischemic and watershed infarctions, and severe progressive occlusive vascular disease developed.

Tracing the Mutation

A thoracic aortic aneurysm/dissection panel was negative, including analysis of ACTA2, and quad genome sequencing was negative.

The Mass General team then detected the de novo single-nucleotide variant in MIR145, enriched in tissues with high smooth muscle cell content. The MIR145 transcript is processed into two microRNAs, and the variant was at nucleotide 3 of miR-145-5p.

Confirming the Connection

The miR-145-5p variant is located within the "seed sequence," a microRNA portion promoting stable interactions with complementary RNAs. The researchers speculated mutant miR-145-5p might not be able to target the regions of messenger RNA that regulate smooth muscle cell function, which could result in cellular effects similar to those of ACTA2 variants.

They exposed human vascular smooth muscle cells to a small interfering RNA targeting miR-145-5p, wild-type miR-145-5p, or the patient's mutant version of miR145-5p. Targeting either miR-145-5p or the mutant miR-145-5p substantially reduced the expression of several cytoskeletal proteins, including transgelin, calponin, and notably, α-SMA.


The MIR145 variant confirms MSMDS to be a disorder of failed smooth muscle cell development and function. Additional loci may be associated with the syndrome, and this case shows the potential of genetic testing for rare diseases that searches beyond protein-coding genes.

Refer a patient to the Department of Neurology

Learn more about Mass General Neuroscience

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