Valproic acid increases SMN levels in spinal muscular atrophy patient cells.
Spinal muscular atrophy (SMA) is an inherited motor neuron disease caused by mutation of the telomeric copy of the survival motor neuron gene (SMN1). Although a centromeric copy of the survival motor neuron gene (SMN2) is retained in all patients with SMA, it differs from SMN1 at a critical nucleotide such that the majority of SMN2 transcripts lack exon 7 and encode an unstable, truncated protein. Here, we show that valproic acid increases levels of exon 7-containing SMN transcript and SMN protein in type I SMA patient-derived fibroblast cell lines. Valproic acid may increase SMN levels both by activating the SMN promoter and by preventing exon 7 skipping in SMN transcripts. Valproic acid and related compounds warrant further investigation as potential treatment for SMA.
Sumner
Charlotte J
CJ
Neurogenetics Branch, National Institute of Neurologic Diseases and Stroke/NIH, Building 10, Room 3B-14, MSC 1250, 10 Center Drive, Bethesda, MD 20892, USA. sumnerc@ninds.nih.gov
Huynh
Thanh N
TN
Markowitz
Jennifer A
JA
Perhac
J Stephen
JS
Hill
Brenna
B
Coovert
Daniel D
DD
Schussler
Kristie
K
Chen
Xiaocun
X
Jarecki
Jill
J
Burghes
Arthur H M
AH
Taylor
J Paul
JP
Fischbeck
Kenneth H
KH
D000927:Anticonvulsants / Q000494:pharmacology*; D002460:Cell Line; D002675:Child, Preschool; D017362:Cyclic AMP Response Element-Binding Protein; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D007223:Infant; D007231:Infant, Newborn; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000187:drug effects*; D011401:Promoter Regions, Genetic; D016601:RNA-Binding Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055532:SMN Complex Proteins; D014897:Spinal Muscular Atrophies of Childhood / Q000235:genetics*; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D014635:Valproic Acid / Q000494:pharmacology*
D000927:Anticonvulsants; D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; C526471:SMN1 protein, human; C526477:SMN2 protein, human; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; D014635:Valproic Acid