Mutations in ANAPC1, Encoding a Scaffold Subunit of the Anaphase-Promoting Complex, Cause Rothmund-Thomson Syndrome Type 1
Mutations in ANAPC1, Encoding a Scaffold Subunit of the Anaphase-Promoting Complex, Cause Rothmund-Thomson Syndrome Type 1
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DOI：
10.1016/j.ajhg.2019.06.011
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发表时间：
2019-09-05
影响因子：
9.8
通讯作者：
Campeau, Philippe M.
中科院分区：
文献类型：
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作者：
Ajeawung, Norbert F.;Thi Tuyet Mai Nguyen;Campeau, Philippe M.
Rothmund-Thomson综合征（RTS）是一种常染色体隐性遗传疾病，其特征是头发稀疏、身材矮小和骨骼异常。2型RTS由RECQL 4中存在双等位基因突变定义，其特征在于癌症易感性增加和骨骼异常，而与青少年白内障相关的1型RTS的遗传基础尚不清楚。我们研究了来自7个家族的10名RTS 1型患者，并在所有受影响的患者中发现了ANAPC 1基因的一个深度内含子剪接突变，该突变是后期促进复合体/环体（APC/C）的一个组成部分，无论是纯合状态还是与另一种突变的反式。成纤维细胞的研究表明，内含子突变导致一个95 bp的假外显子的激活，导致mRNA的提前终止密码子和无义介导的衰变，降低ANAPC 1蛋白水平，并延长间期。有趣的是，敲除突变的杂合子小鼠白内障的发病率增加。我们的研究结果表明，APC/C的缺陷是RTS 1型的原因，并建议APC/C和RECQL 4解旋酶之间可能存在联系，因为这两种蛋白质都参与DNA修复和复制。
Rothmund-Thomson syndrome (RTS) is an autosomal-recessive disorder characterized by poikiloderma, sparse hair, short stature, and skeletal anomalies. Type 2 RTS, which is defined by the presence of bi-allelic mutations in RECQL4, is characterized by increased cancer susceptibility and skeletal anomalies, whereas the genetic basis of RTS type 1, which is associated with juvenile cataracts, is unknown. We studied ten individuals, from seven families, who had RTS type 1 and identified a deep intronic splicing mutation of the ANAPC1 gene, a component of the anaphase-promoting complex/cyclosome (APC/C), in all affected individuals, either in the homozygous state or in trans with another mutation. Fibroblast studies showed that the intronic mutation causes the activation of a 95 bp pseudoexon, leading to mRNAs with premature termination codons and nonsense-mediated decay, decreased ANAPC1 protein levels, and prolongation of interphase. Interestingly, mice that were heterozygous for a knockout mutation have an increased incidence of cataracts. Our results demonstrate that deficiency in the APC/C is a cause of RTS type 1 and suggest a possible link between the APC/C and RECQL4 helicase because both proteins are involved in DNA repair and replication.