Expression of a Diabetes-Related Gene (RAD) in Spinal Muscular Atrophy
Investigators:
- Vicky L. Funanage, PhD
- Mena Scavina, DO
- Wenlan Wang, MD, PhD
Background
Spinal muscular atrophy (SMA), the most common genetic cause of infant mortality, is characterized by severe loss of motor neurons and is associated with muscle weakness and wasting. Deletion or mutations in the survival motor neuron (SMN1) gene, which encodes a protein (SMN) involved in splicing, is the genetic basis for the disease. We are working to understand how deficiency of SMN leads to loss of motor neurons and muscle weakness and wasting. OMIM# 253300
What We're Doing
We are using two different models of SMA to gain insight as to how deficiency of the SMN protein leads to disease. The first model employs cultured skin fibroblast cells and muscle tissue from SMA patients. The second utilizes a mouse model of SMA.
Some of What We've Found
In searching for genes specific to muscle and dysregulated in SMA, we found that mRNA levels for RAD (Ras associated with diabetes) are overexpressed both in skin fibroblasts and muscle from SMA patients. Up-regulation of RAD expression was also observed in muscle from an SMA mouse model. In addition, RAD expression appears to be elevated in muscle from the SMA mice at an early stage after birth and then gradually reduced, while no change was observed in brain tissue.
To understand whether elevated RAD expression in SMA has any effect on cell energy metabolism, we initially conducted glucose uptake experiments in SMA fibroblasts. However, we failed to see any effects because fibroblasts are not sensitive to insulin stimulation. We are currently transforming SMA fibroblasts to muscle cells by a molecular approach and then will revisit this issue.
We are also studying functions of SMN in promoting cell survival. We found that SMA fibroblasts have reduced levels of the full-length SMN transcript but elevated SMN transcript lacking exon 7. We also observed that SMA fibroblasts are more prone to cell death induced by camptothecin than by menadione. We are currently studying the mechanisms by which the SMN protein protects cells from dying.