Spinal muscular atrophy (SMA) is characterized by loss of motor neurons and atrophy of muscle. Proximal SMA is the second most common genetic cause of infant death. As in many neurogenetic disorders, the mutated protein SMN is ubiquitously expressed, yet only a particular type of neuron is affected. SMA is caused by loss of the SMN1 gene and retention of the SMN2 gene, leading to low levels of wild type SMN, which is insufficient for motor neuron survival. Increasing SMN levels by increasing SMN2 copy number modulates the severity of the phenotype. SMN has been reported to bind many proteins including a protein complex responsible for snRNP assembly;however, it has not been clear why reduction of SMN leads to a motor neuron disease. The reduction of SMN levels as opposed to its absence leads to a reduction in the level of certain UsnRNPs in particular U11snRNP in motor neurons. This is predicted to affect the splicing of some genes and their expression. We will use specific genetic mutations to determine the importance of high snRNP assembly and U11snRNP levels to the correction of SMA. Specific patient SMN missense mutations that give rise to alleles that have high or low snRNP assembly activity have been reported. However, in some cases the activity of these alleles for snRNP assembly in cultured cells does not correlate with the severity of the patient. We will create mice that express specific SMN missense mutations that can or cannot perform efficient snRNP assembly to assess the following 1) The correlation of RNP assembly activity and correction of the SMA phenotype in mice. 2) Do any SMN missense alleles function in the absence of low levels of SMN from SMN2? 3) Do SMN missense alleles complement each other or one copy of SMN2 and rescue lethality and correct SMA. This would indicate that SMN functions as an oligomer and that rescue of lethality and SMA involves the same function. 4) Lastly it is important to determine which genes are affected by the reduction RNP function. Understanding how RNP assembly is critically affected in SMA and what genes this affects will define the pathogenesis of the disease and allow for the development and evaluation of an array of targets for therapeutics.
Spinal muscular atrophy (SMA) the most common genetic cause of infant death is caused by reduced levels of the SMN protein.
The aim of this project is to determine and test what function of SMN is disrupted in SMA. This will allow an understanding of the biology of the disease, identification of therapeutic targets and evaluation of therapies.
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