Post date: May 17, 2013 2:52:47 PM

July 3, 2012

Hypoxia is a modifier of SMN2 splicing and disease severity in a severe SMA mouse model.

Bebee TW, Dominguez CE, Samadzadeh-Tarighat S, Akehurst KL, Chandler DS.

Source

The Center for Childhood Cancer at the Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.

Abstract

Spinal muscular atrophy (SMA) is a progressive neurodegenerative disease associated with low levels of the essential Survival Motor Neuron (SMN) protein. Reduced levels of SMN is due to loss of the SMN1 gene and inefficient splicing of the SMN2 gene caused by a C>T mutation in exon 7. Global analysis of the severe SMN7 SMA mouse model revealed altered splicing and increased levels of the hypoxia inducible transcript, Hif3alpha, at late stages of disease progression. Severe SMA patients also develop respiratory deficiency during disease progression. We sought to evaluate whether hypoxia was capable of altering SMN2 exon 7 splicing and if increased oxygenation could modulate disease in a severe SMA mouse model. Hypoxia treatment in cell culture increased SMN2 exon 7 skipping and reduced SMN protein levels. Concordantly, treatment of SMN7 mice with hyperoxia treatment increased inclusion of SMN2 exon 7 in skeletal muscles and resulted in improved motor function. Transfection splicing assays of SMN minigenes under hypoxia revealed hypoxia induced skipping is dependent on poor exon definition due the SMN2 C>T mutation and suboptimal 5'ss. Hypoxia treatment in cell culture led to increased hnRNP A1 and Sam68 levels. Mutation of hnRNP A1 binding sites prevented hypoxia induced skipping of SMN exon 7 and were found to bind both hnRNP A1 and Sam68. These results implicate hypoxic stress as a modulator of SMN2 exon 7 splicing in disease progression and a coordinated regulation by hnRNP A1 and Sam68 as modifiers of hypoxia induced skipping of SMN exon 7.

Published by PubMed.