부산대학교 도서관

Spinal muscular atrophy (SMA) is a motor neuron disease caused by dysfunction of the survival motor neuron (SMN) gene. Human SMNgene is present in duplicated copies: SMN1and SMN2. More than 95% of patients with SMA lack a functional SMN1but retain at least one copy of SMN2. Unlike SMN1, SMN2is 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 SMN2gene 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 5,000μg/ml) and 3 time points (24, 48, and 72 hours). SMN2gene 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 SMN2gene copy number correlated inversely with the SMA phenotypic severity. This study provides the first evidence for a therapeutic indication of hydroxyurea in SMA. Ann Neurol 2005;58:194–202