TRANSCRIPTOME 2002: From Functional Genomics to Systems
Downstream of an RNA Regulatory Protein Causing a Common Human Disease: Expression Profiling Human SMN-Deficient Muscle
Cinzia Brandoli1, Serenella Servidei2, and Eric Hoffman1, 1Children’s National Medical Center, Washington, DC, 2Neurology, Catholic University, Rome, ITALY
Spinal Muscular Atrophy (SMA type 1) is an autosomal recessive neuromuscular disease occurring 1 in 10,000 newborns. While the primary pathological feature of SMA has long been considered to be the loss of the cell bodies of alpha-motor neurons in the anterior horns of the spinal cord, increasing evidence points to important defects of the end target of the motor neurons, namely skeletal muscle. SMA is caused by reduction of the expression of the survival of motor neuron (SMN) gene, which is thought to regulate a series of downstream mRNAs, and the protein is highly concentrated at the neuromuscular junction. Downstream targets have not yet been defined. We describe the use of gene expression profiling of muscle biopsies from human SMA type I infants and age/sex-matched controls to identify genes that were potential downstream targets of SMN mRNA regulation. We found specific transcription factors to be highly down-regulated relative to normal age-matched controls, and disease controls (neonatal Duchenne muscular dystrophy patients). Most striking was a 24-fold under expression of a specific Zinc finger transcription factor of otherwise unknown function. These genes become potential down-stream targets of SMN regulation in muscle.
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