Single Mutation in Non-Coding Gene Linked to Muscle Disorder

[seqadmin]

A new report released in The Journal of Clinical Investigation shows evidence of a single non-coding gene linking back to a rare muscle disease. Researchers from several Massachusetts healthcare institutions collaborated to identify the source of multisystemic smooth muscle dysfunction syndrome (MSMDS) in an individual patient.

MSMDS (OMIM # 613834) is often characterized by smooth muscle across the body, leading to congenital heart defects, cerebrovascular disease, and bladder and intestinal impairments. Previous studies have shown that an R179 missense mutation in the coding gene actin alpha 2 (ACTA2) was primarily associated with MSMD.

One young patient with MSMD had been suffering from multiple strokes that began at three years of age, in addition to bowel, bladder, and feeding issues. After visiting five different hospitals, his family continued to search for a way to help. The physicians began with standard genetic tests, but those examinations didn’t detect the more common mutation in the ACTA2 gene. This prompted a more thorough search from a group of investigators supported by the Undiagnosed Diseases Network (UDN) study.

After analyzing RNA sequencing data obtained from the patient, the team narrowed the problem down to a single nucleotide variant in the microRNA gene, MIR145. The transcript for MIR145 gets processed into 2 microRNAs, and the identified variant was discovered at nucleotide 3 of miR-145-5p.

Follow-up work with tissue culture showed that the variant also affected expression of cytoskeletal proteins and cellular functions of smooth muscle tissue. These cellular changes are similar to those previously described by ACTA2 mutations, which influence smooth muscle behavior.

This new revelation gives the patient’s family hope for treating the condition, which has impacted their son since birth. This study represents one of the few cases where a monogenetic disorder has been linked back to variants in microRNA.

The investigative team is also hopeful for additional NIH funding for the UDN study and would like to perform further searches for rare diseases in non-coding genes like those in microRNA. Enabling work like those performed with the UDN will provide better clinical testing and patient care.