US FDA Grants Expanded Approval of ELEVIDYS Gene Therapy for DMD Patients Ages 4 and Above

SMA Research Briefs: New Gene ID'd, Disease Modifier Explored

Mutations in the DYNC1H1 gene cause a rare form of spinal muscular atrophy; plastin 3 contributes to movement problems in SMN-related SMA

Below are highlights of two recent studies in spinal muscular atrophy (SMA), a disease in which the nerve cells (motor neurons) that control muscles in the spinal cord die, causing progressive weakness in the voluntary muscles.   

Mutations in DYNC1H1 underlie rare form of SMA

Flaws in the tail-end of the cytoplasmic dynein 1 heavy chain 1 (DYNC1H1) gene lead to a rare form of SMA, a team of researchers from the United States and United Kingdom has reported.

The researchers identified three different mutations in the gene that cause dominant SMA-LED, a form of the disease that predominantly affects muscles in the legs. (‘Dominant’ refers to inheritance; it means that only one gene mutation, inherited from one parent, is sufficient to cause the disease.)   

The DYNC1H1 gene, on chromosome 14, carries genetic instructions for production of a protein called dynein. Dynein normally is involved in transporting molecules along the long nerve-cell fibers called axons, through which neurons transmit and receive signals. Dysfunction of the dynein protein affects the development and maintenance of motor neurons and is associated with a range of disorders in people, including type 2O Charcot-Marie-Tooth disease (CMT).

The researchers published their results online March 28, 2012, in Neurology and reported on the study April 24 at the 2012 annual meeting of the American Academy of Neurology in New Orleans. MDA supported Robert Baloh, director of neuromuscular medicine at Cedars-Sinai Medical Center in Los Angeles, and Michael Shy, co-director of the MDA Clinic at University of Iowa Hospitals & Clinics in Iowa City, Iowa, for their contributions to this work.

Decreased levels of plastin 3 correlate with movement problems

It's known that the underlying cause of the most common forms of SMA is a flawed SMN1 gene on chromosome 5 that results in a deficiency of SMN, or survival motor neuron, protein. Now researchers have shown that production of a protein called plastin 3 is dependent on production of SMN; decreased SMN levels correlate with decreased plastin 3 levels, and decreased plastin 3 levels appear to underlie the movement problems characteristic of the disease.

Plastin 3 is considered a disease modifier in SMA. Modifiers don't cause disease but can affect (modify) onset and severity by influencing various biological pathways.

The research team, led by scientists from Ohio State University in Columbus, showed that zebrafish genetically altered to lack SMN had decreased plastin 3 protein levels. The fish exhibited movement problems including difficulty turning and swimming, but partially regained these functions when investigators artificially increased levels of plastin 3.

Increasing plastin 3 did not affect life span in the fish.

In additional studies, the investigators also found:

  • the relationship between SMN and plastin 3 works in only one direction; decreasing plastin 3 levels in healthy zebrafish did not affect SMN levels;
  • stimulating SMN production in zebrafish that initially lacked the protein resulted in an increase in plastin 3 levels;
  • plastin 3 protein levels are not decreased in two other mouse models of motor neuron disease: SOD1-related and TDP43-related amyotrophic lateral sclerosis (ALS).

Examination of motor neurons from the zebrafish with decreased plastin 3 levels revealed damage to axons (the fibers via which nerve cells send and receive signals) and instability in the junction between nerve and muscle cells (neuromuscular junction).

The team, which reported its findings April 11, 2012, in the Journal of Neuroscience, noted that — in addition to plastin 3 — SMN might be affecting the synthesis of other proteins that play a role in SMA.

MDA Resource Center: We’re Here For You

Our trained specialists are here to provide one-on-one support for every part of your journey. Send a message below or call us at 1-833-ASK-MDA1 (1-833-275-6321). If you live outside the U.S., we may be able to connect you to muscular dystrophy groups in your area, but MDA programs are only available in the U.S.

Request Information