Birth defects significantly contribute to childhood morbidity and mortality globally, manifesting as congenital anomalies that lead to severe disabilities in children. These anomalies are the major drivers of infant death rates, prompting extensive research aimed at determining their underlying etiologies to facilitate pre-or-postnatal treatments. However, a clear understanding of the observed abnormalities seen in affected patients remain elusive. To address this gap, a team of researchers at the Regional Centre for Biotechnology (RCB), Faridabad, have generated an animal model through targeted deletion of a key developmental gene in mice.

“The cumulative burden of rare genetic disorders affects millions of people worldwide” says Anju Shukla, Professor and Head, Kasturba Medical College and Hospital, Manipal Academy of Higher Education. She further adds, 

Though several genetic disorders lack a definitive cure, there has been immense progress in the recent times, as more and more of these disorders are becoming amenable to therapy.

In Asian countries, congenital anomalies account for 8 – 15% of perinatal deaths and 13 – 16% of neonatal deaths. Among these birth defects, musculoskeletal congenital disorders stand out due to their capacity to cause severe disabilities in the survivors and impose substantial economic burden on affected families. These musculoskeletal anomalies refer to abnormalities affecting the skeletal and muscular systems present at birth. The reasons behind congenital anomalies vary, and genetic changes are a significant factor. One particular gene, known as MYH3, can undergo mutations that contribute to various human congenital musculoskeletal conditions like Freeman-Sheldon syndrome, Sheldon-Hall syndrome, multiple pterygium syndrome, and spondylocarpotarsal synostosis syndrome (SCTS).

“We aimed to understand the functions of the MYH3 gene by creating a knockout model where this gene is not-functional,” explains Sam J Mathew, Associate Professor, RCB and corresponding author of the study. He adds, 

This approach would also help us to understand and develop potential therapies to target MYH3-associated congenital diseases.

The MYH3 gene provide instructions for making a protein called myosin‑3, which belongs to a protein family responsible for movement and the transport of materials within and between cells, known as myosins. Muscle fibers are primarily composed of thick filaments made up of myosin and thin filaments called actin, involved in muscle contraction. Muscle fibers containing myosin‑3 are primarily present in the foetus before birth, playing a vital role in early muscle development. Myosin proteins function when they are part of a complex. Each such complex consists of two pairs of myosin light chains (produced from other genes), that regulates the complex, and one pair of myosin heavy chains produced by the MYH3 gene.

In this study, the team of researchers developed a mouse model by knocking-out or deleting the MYH3 gene and studied how it affected the adult mice. Their findings revealed that the adult mice displayed traits similar to SCTS, like scoliosis and vertebral fusion. In addition, the adult mice showed reduction in body weight, muscle weight, myofiber size, and grip strength. They also observed changes in the muscle fiber types and increased muscle fibrosis in the mice. Anushree Bharadwaj and Jaydeep Sharma, the authors of the study, explain, ​“Mutations in skeletal muscles expressing myosin genes lead to various congenital musculoskeletal disorders like SCTS. These conditions are not well understood due to the lack of appropriate animal models. While MYH3 expression is primarily seen during embryonic development, our research highlights that its loss of function has significant implications during adulthood as well.”

The authors used a range of cellular and molecular biology assays, along with mass spectrometry experiments. Their study revealed a notable activation of a transcriptional regulator called Yes-associated protein (YAP) within the skeletal muscle of the knockout mouse model. Looking ahead to future research directions, Mathew adds, ​“This identification of the YAP signalling pathway as a potential therapeutic target in MYH3 associated musculoskeletal disorders is novel and of immense interest, which should be further explored using human patient samples and clinical studies”.

“The work carried out by Mathew and his team is an important milestone in advancing our understanding of rare genetic disorders,” says Shukla. She expresses optimism about witnessing impactful contributions from Indian institutes in this field.