New type of muscular dystrophy discovered after girl’s diagnosis

The disorder arises from mutations in the SNUPN gene

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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Researchers have discovered a new, unrecognized type of muscular dystrophy that’s caused by inherited mutations in the SNUPN gene, a study reports.

Most people who carry the mutations develop symptoms of muscle weakness before age 2, and the muscles of the upper arms and legs are mainly affected.

“This study represents a significant leap forward in our understanding and diagnosis of muscular dystrophies,” co-author Nathalie Escande Beillard, PhD, an assistant professor at the Koç University School of Medicine, Turkey said in a university press release. The study, “SNUPN deficiency causes a recessive muscular dystrophy due to RNA mis-splicing and ECM dysregulation,” was published in Nature Communications.

Muscular dystrophies (MDs) are a group of inherited disorders marked by progressive muscle weakness due to the degeneration of muscle fibers. More than 30 types of muscular dystrophy have been identified, all with different causes.

Recently, a young girl from a Kosovar family was diagnosed with muscular dystrophy by clinicians at the Koç University Hospital.

At age 5, the girl began falling and developed an abnormal walk, which worsened over time. Tests detected muscle weakness, evidence of muscle disease, and elevated blood levels of creatinine kinase, a sign of muscle damage. Genetic mutations associated with known types of muscular dystrophy weren’t detected in standard screens, however.

A more extensive genetic assessment revealed a previously unreported mutation in both copies of the SNUPN gene, which provides instructions for the Snurportin-1 protein, or SPN1, which aids in processing RNA for protein production. According to the researchers, “SPN1 has never been associated with a human disease.”

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Finding others with SNUPN gene mutations

To better understand SPN1’s function and its connection to muscular dystrophy, the scientists used genetic databanks to identify and recruit 17 others with SNUPN mutations across 11 countries. Among the 10 males and eight females, 12 (67%) presented with symptoms before age 2, with various degrees of progressive muscle weakness. All showed weakness in the muscles of the upper arms and legs, and less often in the core muscles or those of the outer limbs. Ten of them lost the ability to walk without assistance.

Tests showed signs of consistent muscular dystrophy, including elevated creatinine kinase and muscle fiber damage. All the patients also had at least one symptom that affected either the nervous system, the eyes, the skeleton, or the lungs.

Disease progression and severity varied. Eleven patients developed breathing difficulties that required assistance and two died of lung failure before age 15.

A detailed genetic analysis revealed nine distinct disease-causing SNUPN gene mutations among the 18 affected people, who showed a broad range of muscular weakness.

“These findings provide strong clinical, histological [tissue], and genetic evidence to support the causal association between SNUPN variants and a previously uncharacterized subtype of muscular dystrophy disorder,” the researchers wrote.

Eight of the nine disease-causing SNUPN mutations were found to alter the far end of the SPN1 protein chain, called the C-terminus. These alterations affected the protein’s ability to form complexes with itself, disrupting its stability and proper function.

In patient-derived cells, the SNUPN mutations appeared to lead to a deficiency in SPN protein caused by its instability and subsequent degradation. A SPN1 deficiency was then shown to prevent the import of proteins into the nucleus that interact with a larger protein complex called SMN, which is essential for processing RNA for protein production.

Mutations in the gene that encodes the SMN1 protein, a key component of the SMN complex, cause spinal muscle atrophy (SMA), a rare disease that features progressive muscle weakness and atrophy.

Consistently, a lack of SPN1 disrupted the regulation of RNA processing and protein production, and affected components of the sarcolemma, the cellular membrane that surrounds muscle fibers. In particular, the organization of the cytoskeleton, a network of protein filaments within a cell that provides structural support, was affected.

In Duchenne muscular dystrophy (DMD), the most common type of muscular dystrophy, mutations in the DMD gene lead to a lack of dystrophin protein, which also damages the sarcolemma.

“Our study has uncovered shared underlying [disease-causing mechanisms] between SPN1-deficient patients and other types of muscular dystrophies,” the researchers said. “These findings suggest that targeting SPN1 … may hold promise as a therapeutic approach” and “pave the way for the development of effective treatments for individuals with MDs.”

“Our findings underscore for the first time the critical role of the Snurportin-1 protein encoded by the SNUPN gene in maintaining the structural integrity and function of muscle cells,” Beillard said.