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首页> 外文期刊>American journal of medical genetics, Part A >Circadian abnormalities in mouse models of Smith-Magenis syndrome: evidence for involvement of RAI1.
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Circadian abnormalities in mouse models of Smith-Magenis syndrome: evidence for involvement of RAI1.

机译：史密斯 - Magenis综合征小鼠模型中的昼夜昼夜异常：RAI1参与的证据。

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Smith-Magenis syndrome (SMS; OMIM 182290) is a genomic disorder characterized by multiple congenital anomalies, intellectual disability, behavioral abnormalities, and disordered sleep resulting from an ~3.7 Mb deletion copy number variant (CNV) on chromosome 17p11.2 or from point mutations in the gene RAI1. The reciprocal duplication of this region results in another genomic disorder, Potocki-Lupski syndrome (PTLS; OMIM 610883), characterized by autism, intellectual disability, and congenital anomalies. We previously used chromosome-engineering and gene targeting to generate mouse models for PTLS (Dp(11)17/+), and SMS due to either deletion CNV or gene knock-out (Df(11)17-2/+ and Rai1(+/-) , respectively) and we observed phenotypes in these mouse models consistent with their associated human syndromes. To investigate the contribution of individual genes to the circadian phenotypes observed in SMS, we now report the analysis of free-running period lengths in Rai1(+/-) and Df(11)17-2/+ mice, as well as in mice deficient for another known circadian gene mapping within the commonly deleted/duplicated region, Dexras1, and we compare these results to those previously observed in Dp(11)17/+ mice. Reduced free-running period lengths were seen in Df(11)17-2/+, Rai1(+/-) , and Dexras1(-/-) , but not Dexras1(+/-) mice, suggesting that Rai1 may be the primary gene underlying the circadian defects in SMS. However, we cannot rule out the possibility that cis effects between multiple haploinsufficient genes in the SMS critical interval (e.g., RAI1 and DEXRAS1) either exacerbate the circadian phenotypes observed in SMS patients with deletions or increase their penetrance in certain environments. This study also confirms a previous report of abnormal circadian function in Dexras1(-/-) mice.
机译：Smith-Magenis综合征（SMS; OMIM 182290）是一种基因组疾病，其特征在于多重先天性异常，智力残疾，行为异常，患有〜3.7 MB缺失拷贝数变体（CNV）17p11.2或点引起的睡眠。基因Rai1中的突变。该区域的互核复制导致另一个基因组疾病，Potocki-Lupski综合征（PTLS; OMIM 610883），其特征在于自闭症，智力残疾和先天性异常。我们以前使用染色体工程和基因靶向为PTL的小鼠模型（DP（11）17 / +）和由于缺失CNV或基因敲除引起的SMS（DF（11）17-2 / +和RAI1（分别+/-），我们观察到这些小鼠模型中的表型与其相关的人类综合征一致。要调查单个基因对SMS中观察到的昼夜活动表型的贡献，我们现在报告了RAI1（+/-）和DF（11）17-2 / +小鼠以及小鼠的自由运行期长度的分析缺乏在常用/重叠区域，DEXRAS1内的另一种已知的昼夜基因映射，并且我们将这些结果与先前在DP（11）17 / +小鼠中观察到的那些结果进行比较。在DF（11）17-2 / +，RAI1（+/-）和DEXRAS1（ - / - ）中看到减少的自由运行周期长度，但不是DEXRAS1（+/-）小鼠，表明RAI1可能是SMS中昼夜节律缺陷的主要基因。然而，我们不能排除SMS临界间隔（例如，RAI1和DEXRAS1）中多种单速低量基因之间的CIS效应的可能性加剧了短期内观察到的SMS患者在某些环境中观察到的SMS患者的昼夜型表型。本研究还证实了德克萨斯州1（ - / - ）小鼠中异常昼夜节律功能的报告。

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