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Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder characterized by muscle wasting due to the degeneration of the motor neurons in the anterior horn of the spinal cord. SMA is incurable and is one of the leading genetic causes of infant death worldwide with many children dying before the age of two. Recessive mutations in the SMN1 gene, and subsequent deficiency of the SMN protein, cause the disease. All patients retain on one or more copies of SMN2, an inverted duplication of SMN1. SMN2 pre-mRNA is alternatively spliced to primarily produce a non-functional truncated SMN protein that is rapidly degraded. SMN2 does, however, produce low levels of the functional full length SMN protein.
Given that SMN2 produces some full-length SMN protein, increasing these baseline levels may be a mechanism to ameliorate the SMA phenotype. Understanding genes that modulate SMN protein levels is one approach to developing treatments for SMA. We thus performed a genome-wide RNAi screen using a cell line stably expressing a SMN-luciferase reporter to identify new candidate SMN modulators. We were then able to effectively knockdown the top four candidate genes from the RNAi screen (SRSF3, UBA7, CPSF1 and WDR33) in SMA patient-derived fibroblasts cells. We observed increased SMN protein levels for SRSF3, UBA7, CPSF1 and WDR33 knockdowns, validating results from the RNAi screen. Lastly, we were able to suggest that SRSF3 likely modulates SMN splicing while none of the genes investigated affect SMN transcription.
Last Modified December 14, 2012