What is it about?
X-linked spinal muscular atrophy (XL-SMA) results from mutations in the Ubiquitin-Like Modifier Activating Enzyme 1 (UBA1). It is a form of spinal muscular atrophy very similar to the autosomal recessive form on chromosome 5, except this form only effects males (usually very early in life), and many of the affected males also have congenital contractures. In 2008, our research group detected the first disease-causing mutations.in a gene UBA-1. These mutations, three missense and one synonymous, all lie within Exon15 of the UBA1 gene, which contains the active adenylation domain (AAD). In this work, we describe the first investigations of possible pathogenic effects of the three known missense variants in vitro using a novel Uba1 activity assay and other methods.
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Why is it important?
Our results demonstrate a surprising shift from the likelihood of these XL-SMA mutations playing a damaging role in Uba1’s enzymatic activity with Ubiquitin, to other roles such as altering Uba1 mRNA splicing via the disruption of splicing factor binding sites, similar to a mechanism in traditional SMA, or disrupting binding to other important in vivo binding partners. These findings help narrow down the number of possibilities of dysfunction of the Uba1 network, which result in XL-SMA. Moreover, this investigation provides additional critical understanding of the mutations’ biochemical mechanisms, vital for the development of future effective diagnostic assays and therapeutics.
Perspectives
We were surprised by the findings (at least in vitro), the mutations did not exert any negative effects on Uba1 adenylation, thioester, and transthioesterification steps crucial to activate Ubiquitin binging and transfer to downstream E2 ligase. Of course, these experiments need to be repeated in vivo (either in patient cell lines or in IPS cells), which will be the obvious next investigations to be performed. Because the experiments performed in this paper were al done in vitro, it may well be that as this experiments are repeated in vivo, we may find detrimental effects on important binding partners not seen through the in vitro studies described in this publication.
Lisa Baumbach-Reardon
University of Medical Sciences Arizona
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This page is a summary of: Functional characterizations of rare UBA1 variants in X-linked Spinal Muscular Atrophy, F1000Research, September 2017, Faculty of 1000, Ltd.,
DOI: 10.12688/f1000research.11878.1.
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