What is the role of alternative splicing in disease?

Alternative splicing can lead to disease by producing abnormal proteins that disrupt cellular processes.

Alternative splicing is a mechanism by which different combinations of exons in a pre-mRNA are spliced together to generate multiple mRNA isoforms. This process is essential for generating protein diversity and regulating gene expression. However, aberrant splicing events can lead to the production of abnormal proteins that disrupt cellular processes and contribute to disease.

One example of alternative splicing in disease is spinal muscular atrophy (SMA), a genetic disorder that affects the motor neurons in the spinal cord. SMA is caused by mutations in the SMN1 gene, which encodes the survival motor neuron (SMN) protein. Alternative splicing of the SMN2 gene produces a truncated version of the SMN protein that is less stable and less functional than the full-length protein. This results in a deficiency of SMN protein in motor neurons, leading to their degeneration and muscle weakness.

Another example is cancer, where alternative splicing can contribute to tumour progression and drug resistance. Aberrant splicing events can generate isoforms of oncogenes or tumour suppressor genes that have altered functions or expression patterns. For example, the Bcl-2 family of proteins regulates apoptosis, and alternative splicing can produce isoforms that either promote or inhibit cell death. This can affect the response of cancer cells to chemotherapy and other treatments.

In conclusion, alternative splicing plays a crucial role in regulating gene expression and protein diversity, but aberrant splicing events can contribute to disease. Understanding the mechanisms of alternative splicing and its impact on cellular processes is essential for developing new therapies for genetic disorders and cancer.