Congenital lethal motor neuron disease with a novel defect in ribosome biogenesis
- Butterfield, R.J., Stevenson, T.J., Xing, L., Newcomb, T.M., Nelson, B., Zeng, W., Li, X., Lu, H.M., Lu, H., Farwell Gonzalez, K.D., Wei, J.P., Chao, E.C., Prior, T.W., Snyder, P.J., Bonkowsky, J.L., Swoboda, K.J.
- Neurology 82: 1322-30 (Journal)
- Registered Authors
- Bonkowsky, Joshua, Li, Xiang
- MeSH Terms
- Infant, Newborn
- Muscular Atrophy, Spinal/congenital
- Muscular Atrophy, Spinal/genetics*
- Muscular Atrophy, Spinal/metabolism
- Nuclear Proteins/genetics*
- Nuclear Proteins/metabolism
- 24647030 Full text @ Neurology
Butterfield, R.J., Stevenson, T.J., Xing, L., Newcomb, T.M., Nelson, B., Zeng, W., Li, X., Lu, H.M., Lu, H., Farwell Gonzalez, K.D., Wei, J.P., Chao, E.C., Prior, T.W., Snyder, P.J., Bonkowsky, J.L., Swoboda, K.J. (2014) Congenital lethal motor neuron disease with a novel defect in ribosome biogenesis. Neurology. 82:1322-30.
Objective We describe a novel congenital motor neuron disease with early demise due to respiratory insufficiency with clinical overlap with spinal muscular atrophy with respiratory distress (SMARD) type 1 but lacking a mutation in the IGHMBP2 gene.
Methods Exome sequencing was used to identify a de novo mutation in the LAS1L gene in the proband. Pathogenicity of the mutation was validated using a zebrafish model by morpholino-mediated knockdown of las1l.
Results We identified a de novo mutation in the X-linked LAS1L gene in the proband (p.S477N). The mutation is in a highly conserved region of the LAS1L gene predicted to be deleterious by bioinformatic analysis. Morpholino-based knockdown of las1l, the orthologous gene in zebrafish, results in early lethality and disruption of muscle and peripheral nerve architecture. Coinjection of wild-type but not mutant human RNA results in partial rescue of the phenotype.
Conclusion We report a patient with a SMARD phenotype due to a mutation in LAS1L, a gene important in coordinating processing of the 45S pre-rRNA and maturation of the large 60S ribosomal subunit. Similarly, the IGHMB2 gene associated with SMARD type 1 has been suggested to have an important role in ribosomal biogenesis from its role in processing the 45S pre-rRNA. We propose that disruption of ribosomal maturation may be a common pathogenic mechanism linking SMARD phenotypes caused by both IGHMBP2 and LAS1L.
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes