Schimke immuno-osseous dysplasia: SMARCAL1 loss-of-function and phenotypic correlation
Schimke immuno-osseous dysplasia: SMARCAL1 loss-of-function and phenotypic correlation
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DOI：
10.1136/jmg.2008.060095
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发表时间：
2009-01-01
影响因子：
4
通讯作者：
Boerkoel, C. F.
中科院分区：
文献类型：
--
作者：
Elizondo, L. I.;Cho, K. S.;Boerkoel, C. F.
背景：Schimke免疫骨性发育不良（SIOD）是由SMARCAL1基因突变引起的常染色体隐性多益性疾病。SMARCAL1编码一种与SNF2染色质重塑蛋白同源的酶。方法：为了评估与SIOD相关的SMARCAL1突变对SMARCAL1表达和功能的影响，我们表征了各种突变对患者组织和细胞系中mRNA和蛋白质表达的影响，以及SMARCAL1错义突变体的atp酶活性、亚细胞定位和染色质结合。结果：SIOD相关的SMARCAL1突变影响了SMARCAL1蛋白的表达、稳定性、亚细胞定位、染色质结合和酶活性。此外，在黑腹果蝇中表达SMARCAL1错义突变体表明，疾病严重程度与SMARCAL1的总体活性成反比。结论：我们的研究结果首次表明，SMARCAL1在体内与染色质结合，SIOD是由SMARCAL1多种功能受损引起的。
Background: Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive pleiotropic disorder caused by mutations in SMARCAL1. SMARCAL1 encodes an enzyme with homology to the SNF2 chromatin remodelling proteins.Methods: To assess the affect of SMARCAL1 mutations associated with SIOD on SMARCAL1 expression and function, we characterised the effects of various mutations on mRNA and protein expression in patient tissues and cell lines, and the ATPase activity, subcellular localisation, and chromatin binding of SMARCAL1 missense mutants.Results: The SIOD associated SMARCAL1 mutations affected SMARCAL1 protein expression, stability, subcellular localisation, chromatin binding, and enzymatic activity. Further, expressing SMARCAL1 missense mutants in Drosophila melanogaster showed that disease severity was inversely proportionate to overall SMARCAL1 activity.Conclusion: Our results show for the first time that SMARCAL1 binds chromatin in vivo and that SIOD arises from impairment of diverse SMARCAL1 functions.