Penetrance of biallelic SMARCAL1 mutations is associated with environmental and genetic disturbances of gene expression
Penetrance of biallelic SMARCAL1 mutations is associated with environmental and genetic disturbances of gene expression
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DOI：
10.1093/hmg/dds083
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发表时间：
2012-06-01
影响因子：
3.5
通讯作者：
Boerkoel, Cornelius F.
中科院分区：
文献类型：
--
作者：
Baradaran-Heravi, Alireza;Cho, Kyoung Sang;Boerkoel, Cornelius F.
DNA退火解旋酶SMARCAL 1（SWI/SNF相关、基质相关、肌动蛋白依赖性染色质调节因子，亚家族a样1）的双等位基因突变导致Schimke免疫性骨发育不良（SIOD，MIM 242900），一种不完全外显的常染色体隐性遗传病。使用人类，果蝇和小鼠模型，我们表明，SMARCAL 1同源基因编码的蛋白定位于转录活性染色质和调节基因表达。我们还表明，如在SIOD患者中发现的，SMARCAL 1直系同源物单独缺乏不足以引起果蝇和小鼠的疾病，尽管这种缺乏会导致基因表达的适度弥漫性改变。相反，当SMARCAL 1缺陷与遗传和环境因素相互作用时，疾病就会表现出来，从而进一步改变基因表达。我们的结论是SMARCAL 1退火解旋酶缓冲基因表达的波动，基因表达的改变有助于SIOD的逆转。
Biallelic mutations of the DNA annealing helicase SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1) cause Schimke immuno-osseous dysplasia (SIOD, MIM 242900), an incompletely penetrant autosomal recessive disorder. Using human, Drosophila and mouse models, we show that the proteins encoded by SMARCAL1 orthologs localize to transcriptionally active chromatin and modulate gene expression. We also show that, as found in SIOD patients, deficiency of the SMARCAL1 orthologs alone is insufficient to cause disease in fruit flies and mice, although such deficiency causes modest diffuse alterations in gene expression. Rather, disease manifests when SMARCAL1 deficiency interacts with genetic and environmental factors that further alter gene expression. We conclude that the SMARCAL1 annealing helicase buffers fluctuations in gene expression and that alterations in gene expression contribute to the penetrance of SIOD.