Researchers Identify Gene for Rare Form of Spinal Muscular Atrophy
TUCSON, Ariz. — Flaws in a gene known as UBE1 have been identified as the cause of a rare, X-chromosome-linked form of spinal muscular atrophy (SMA), a severe neurodegenerative disease, the Muscular Dystrophy Association (MDA) announced today.
Lisa Baumbach-Reardon, an associate research professor and head of the Neurogenetics Laboratory at the University of Miami (Fla.), who received MDA support for this work, led the study team with Alfons Meindl at Technical University Munich (Germany). The researchers published their findings in today’s issue of the American Journal of Human Genetics.
Having a second gene identified that causes symptoms of SMA is extremely important, not only for the development of better diagnostic tests but also for the development of new animal models and new therapeutic approaches,” said Sharon Hesterlee, MDA vice president for translational research.
The vast majority of SMA cases are caused by a mutation in the SMN1 gene on chromosome 5, which was identified in the mid-1990s. The chromosome-5 form of the disease affects both sexes and ranges in severity from the very severe and often-fatal infantile-onset form (type 1) to the somewhat less severe forms, type 2 and type 3.
The X-chromosome form of the disease, which affects male babies, occurs in a small percentage of SMA cases. Its exact incidence is unknown.
The disease closely resembles the type 1, chromosome-5 form of SMA in all respects except that it also affects the joints, which are not affected in chromosome-5 SMA.
The X-linked disease, which is present at birth, results in low muscle tone, absent reflexes, and multiple contractures (frozen joints) in association with loss of muscle-controlling nerve cells (motor neurons) in the spinal cord. It leads to death within two years.
The underlying genetic cause is any of a number of abnormalities (mutations) in a gene on the X chromosome that carries instructions for “ubiquitin-activating enzyme E1” (UBE1). This enzyme’s normal job in cells is to help attach ubiquitin molecules to proteins the cell needs to destroy. The ubiquitin “tag” marks proteins for destruction. Altered function of this protein disposal system is the likely mechanism by which X-linked SMA occurs.
The investigators screened four North American, one Mexican and one Thai family in which X-linked SMA was suspected and compared their X chromosomes to X chromosomes from unaffected people.
They screened 3,550 chromosomes from unaffected people for two of the UBE1 mutations suspected of causing X-linked SMA and found no instances of either mutation. A third suspected mutation in the same gene was not found in 7,914 chromosomes from people without the disease.
“This study is the culmination of 15 years of investigation, starting with identification of the first families with X-linked SMA, through years of gene-mapping studies to finally, last year, gene discovery and mutation identification.
“It’s been a long road, but we never gave up, because we promised the families who have this devastating illness that, with their participation in our research studies, we would someday identify the causal disease gene,” Baumbach-Reardon said. “Along the way, we’ve worked with an international team of geneticists, genetic counselors and scientists. We all share in the excitement and the hope that this discovery brings.”
About MDA
MDA is a voluntary health agency working to defeat more than 40 neuromuscular diseases, including SMA, through programs of worldwide research, comprehensive services, and far-reaching professional and public health education. For more information, visit http://www.mda.org.
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