Spinal muscular atrophy with respiratory distress type 1 (
SMARD1) is a fatal motoneuron disorder in children with unknown etiology. The disease is caused by mutations in the IGHMBP2 gene, encoding a Super Family 1 (SF1)-type
RNA/
DNA helicase. IGHMBP2 is a cytosolic
protein that binds to ribosomes and polysomes, suggesting a role in
mRNA metabolism. Here we performed morphological and functional analyses of isolated
immunoglobulin μ-
binding protein 2 (Ighmbp2)-deficient motoneurons to address the question whether the
SMARD1 phenotype results from de-regulation of protein biosynthesis. Ighmbp2-deficient motoneurons exhibited only moderate morphological aberrations such as a slight increase of axonal branches. Consistent with the rather mild phenotypic aberrations,
RNA sequencing of Ighmbp2-deficient motoneurons revealed only minor transcriptome alterations compared to controls. Likewise, we did not detect any global changes in
protein synthesis using pulsed SILAC (Stable
Isotope Labeling by
Amino acids in Cell culture), FUNCAT (FlUorescent Non-Canonical
Amino acid Tagging) and SUnSET (SUrface SEnsing of Translation) approaches. However, we observed reduced β-actin
protein levels at the growth cone of Ighmbp2-deficient motoneurons which was accompanied by reduced level of IMP1/ZBP1, a known interactor of β-actin
mRNA. Fluorescence Recovery after Photobleaching (FRAP) studies revealed translational down-regulation of an eGFP-myr-β-actin
3'UTR mRNA in growth cones. Local translational regulation of β-actin
mRNA was dependent on the
3' UTR but independent of direct Ighmbp2-binding to β-actin
mRNA. Taken together, our data indicate that Ighmbp2 deficiency results in local but modest disruption of protein biosynthesis which might partially contribute to the motoneuron defects seen in
SMARD1.