Posted - February 2014 in Research Highlights
ALS2 mutations cause ALS, PLS or HSP
23 different mutations of the ALS2 gene causing motor neurone disease, primary lateral sclerosis and hereditary spastic paraplegia have so far been described. This new Saudi study has identified a new ALS2 mutation causing infantile-onset ascending HSP in two children.
Recessive mutations in the alsin gene cause three clinically distinct motor neuron diseases: juvenile amyotrophic lateral sclerosis (ALS2), juvenile primary lateral sclerosis (JPLS) and infantile-onset ascending hereditary spastic paraplegia (IAHSP). A total of 23 different ALS2 mutations have been described for the three disorders so far.
Most of these mutations result in a frameshift leading to a premature truncation of the alsin protein. We report the novel ALS2 truncating mutation c.2761C>T; p.R921X detected by homozygosity mapping and sequencing in two infants affected by IAHSP with bulbar involvement. The mutation c.2761C>T resides in the pleckstrin domain, a characteristic segment of guanine nucleotide exchange factors of the Rho GTPase family, which is involved in the overall neuronal development or maintenance.
This study highlights the importance of using homozygosity mapping combined with candidate gene analysis to identify the underlying genetic defect as in this Saudi consanguineous family.
SOURCE: Gene. 2014 Feb 15;536(1):217-20. doi: 10.1016/j.gene.2013.11.043. Epub 2013 Dec 4. Copyright © 2013 Elsevier B.V. All rights reserved. PMID: 24315819 (PubMed – in process)
Infantile-onset ascending hereditary spastic paraplegia with bulbar involvement due to the novel ALS2 mutation c.2761C>T.
Wakil SM1, Ramzan K2, Abuthuraya R2, Hagos S2, Al-Dossari H2, Al-Omar R2, Murad H3, Chedrawi A3, Al-Hassnan ZN4, Finsterer J5, Bohlega S3.
1 Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
2 Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
3 Department of Neurosciences, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
4 Department of Medical Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
5 Krankenanstalt Rudolfstiftung, Vienna, Austria.