Hydroxyurea enhances SMN2 gene expression in spinal muscular atrophy cells

Ann Neurol. 2005 Aug;58(2):194-202. doi: 10.1002/ana.20548.


Spinal muscular atrophy (SMA) is a motor neuron disease caused by dysfunction of the survival motor neuron (SMN) gene. Human SMN gene is present in duplicated copies: SMN1 and SMN2. More than 95% of patients with SMA lack a functional SMN1 but retain at least one copy of SMN2. Unlike SMN1, SMN2 is primarily transcribed into truncated messenger RNA and produces low levels of SMN protein. We tested a therapeutic strategy by treating cultured lymphocytes from patients with SMA with hydroxyurea to modify SMN2 gene expression and to increase the production of SMN protein. Twenty lymphoblastoid cell lines (15 SMA and 5 control lines) were treated with hydroxyurea at 5 concentrations (0.5, 5, 50, 500, and 5,000 microg/ml) and 3 time points (24, 48, and 72 hours). SMN2 gene copy numbers were determined using real-time quantitative polymerase chain reaction. Hydroxyurea treatment resulted in a time-related and dose-dependent increase in the ratio of full-length to truncated SMN messenger RNA. SMN protein levels and intranuclear gems also were significantly increased in these hydroxyurea-treated cells. The SMN2 gene copy number correlated inversely with the SMA phenotypic severity. This study provides the first evidence for a therapeutic indication of hydroxyurea in SMA.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology*
  • Gene Dosage
  • Gene Expression / drug effects*
  • Gene Expression Regulation / drug effects
  • Humans
  • Hydroxyurea / pharmacology*
  • Immunohistochemistry / methods
  • Lymphocytes / drug effects*
  • Lymphocytes / metabolism
  • Motor Neurons / drug effects
  • Motor Neurons / metabolism
  • Muscular Atrophy, Spinal / classification
  • Muscular Atrophy, Spinal / genetics*
  • Muscular Atrophy, Spinal / pathology
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction / methods
  • SMN Complex Proteins
  • Survival of Motor Neuron 1 Protein
  • Survival of Motor Neuron 2 Protein
  • Time Factors


  • Cyclic AMP Response Element-Binding Protein
  • Enzyme Inhibitors
  • GEMIN2 protein, human
  • Nerve Tissue Proteins
  • RNA, Messenger
  • RNA-Binding Proteins
  • SMN Complex Proteins
  • SMN1 protein, human
  • SMN2 protein, human
  • Survival of Motor Neuron 1 Protein
  • Survival of Motor Neuron 2 Protein
  • Hydroxyurea