A team of researchers at Nationwide Children's Hospital may have found a biological explanation of why low levels of oxygen advance spinal muscular atrophy (SMA) symptoms and oxygen treatments extend life expectancy.
Respiratory support is one of the most common treatment options for severe SMA patients since respiratory deficiencies increase as the disease progresses. Clinicians have found that successful oxygen support can allow patients with severe SMA to live longer. However, the biological relationship between SMA symptoms and low oxygen levels isn't clear. To better understand this relationship, investigators at Nationwide Children's Hospital examined gene expression within a mouse model of severe SMA.
"We questioned whether low levels of oxygen linked to biological stress is a component of SMA disease progression and whether these low oxygen levels could influence how the SMN2 gene is spliced," says Dawn Chandler, PhD, principal investigator in the Center for Childhood Cancer and Blood Diseases at The Research Institute at Nationwide Children's Hospital.
Mouse models of severe SMA have shown changes in how genes are differentially spliced and expressed as the disease progresses, especially near end-stages. "One gene that undergoes extreme alteration is Hif3alpha," says Dr. Chandler. "This is a stress gene that responds to changes in available oxygen in the cellular environment, specifically to decreases in oxygen. This gave us a clue that low levels of oxygen might influence how the SMN2 gene is spliced."
Upon examining mouse models of severe SMA exposed to low oxygen levels, Dr. Chandler's team found that SMN2 exon 7 skipping increased within skeletal muscles. When the mice were treated with higher oxygen levels, exon 7 was included more often and the mice showed signs of improved motor function.
Results appear in the latest issue of Human Molecular Genetics.
Respiratory support is one of the most common treatment options for severe SMA patients since respiratory deficiencies increase as the disease progresses. Clinicians have found that successful oxygen support can allow patients with severe SMA to live longer. However, the biological relationship between SMA symptoms and low oxygen levels isn't clear. To better understand this relationship, investigators at Nationwide Children's Hospital examined gene expression within a mouse model of severe SMA.
"We questioned whether low levels of oxygen linked to biological stress is a component of SMA disease progression and whether these low oxygen levels could influence how the SMN2 gene is spliced," says Dawn Chandler, PhD, principal investigator in the Center for Childhood Cancer and Blood Diseases at The Research Institute at Nationwide Children's Hospital.
Mouse models of severe SMA have shown changes in how genes are differentially spliced and expressed as the disease progresses, especially near end-stages. "One gene that undergoes extreme alteration is Hif3alpha," says Dr. Chandler. "This is a stress gene that responds to changes in available oxygen in the cellular environment, specifically to decreases in oxygen. This gave us a clue that low levels of oxygen might influence how the SMN2 gene is spliced."
Upon examining mouse models of severe SMA exposed to low oxygen levels, Dr. Chandler's team found that SMN2 exon 7 skipping increased within skeletal muscles. When the mice were treated with higher oxygen levels, exon 7 was included more often and the mice showed signs of improved motor function.
Results appear in the latest issue of Human Molecular Genetics.
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