Defective DNA Polymerase α-Primase Leads to X-Linked Intellectual Disability Associated with Severe Growth Retardation, Microcephaly, and Hypogonadism.
Defective DNA Polymerase α-Primase Leads to X-Linked Intellectual Disability Associated with Severe Growth Retardation, Microcephaly, and Hypogonadism.
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有缺陷的 DNA 聚合酶 α-引物酶会导致与严重生长迟缓、小头畸形和性腺功能减退症相关的 X 连锁智力障碍。
DOI：
10.1016/j.ajhg.2019.03.006
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发表时间：
2019
影响因子：
9.8
通讯作者：
Jaeken,Jacqu
中科院分区：
文献类型：
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作者：
VanEsch,Hilde;Colnaghi,Rita;Freson,Kathleen;Starokadomskyy,Petro;Zankl,Andreas;Backx,Liesbeth;Abramowicz,Iga;Outwin,Emily;Rohena,Luis;Faulkner,Claire;Leong,GaryM;Newbury-Ecob,RuthA;Challis,RachelC;Õunap,Katrin;Jaeken,Jacqu
高效而准确地复制人类基因组是一项艰巨的挑战，涉及超过30亿个碱基对的复制。完成这一任务的复杂机制的核心是DNA聚合酶B家族的三个成员：DNA聚合酶α、δ和ε。这些多聚体聚合酶共同确保DNA复制以接近2 × 103个核苷酸/分钟的最佳速率进行，错误率小于每百万个聚合核苷酸中的一个。未受损DNA的大部分DNA复制是由DNA聚合酶δ和ε进行的。DNA聚合酶α-引发酶复合物进行有限的合成以启动复制过程，沿着冈崎片段在不连续的滞后链上合成。到目前为止，已经描述了越来越多的由DNA复制装置的不同组件中的缺陷引起的人类疾病。这些是临床上多样化的，涉及广泛的特征，包括生长延迟，免疫缺陷，内分泌失调，脂肪营养不良和癌症易感性的可变组合。在此，通过使用各种互补的方法，包括经典的连锁分析，靶向的下一代测序，和全外显子组测序，我们描述了不同的错义和剪接影响突变POLA 1在5个不相关的家庭提出了一个X连锁综合征涉及智力残疾，比例矮小，小头畸形，性腺功能减退。POLA 1编码的p180催化亚基的DNA聚合酶α-引物酶。一系列的复制障碍，可以证明在淋巴母细胞系来自受影响的个人。我们的研究结果描述了B家族DNA聚合酶成员DNA聚合酶α的催化组分中的致病性突变的呈现。
Replicating the human genome efficiently and accurately is a daunting challenge involving the duplication of upward of three billion base pairs. At the core of the complex machinery that achieves this task are three members of the B family of DNA polymerases: DNA polymerases α, δ, and ε. Collectively these multimeric polymerases ensure DNA replication proceeds at optimal rates approaching 2 × 103nucleotides/min with an error rate of less than one per million nucleotides polymerized. The majority of DNA replication of undamaged DNA is conducted by DNA polymerases δ and ε. The DNA polymerase α-primase complex performs limited synthesis to initiate the replication process, along with Okazaki-fragment synthesis on the discontinuous lagging strand. An increasing number of human disorders caused by defects in different components of the DNA-replication apparatus have been described to date. These are clinically diverse and involve a wide range of features, including variable combinations of growth delay, immunodeficiency, endocrine insufficiencies, lipodystrophy, and cancer predisposition. Here, by using various complementary approaches, including classical linkage analysis, targeted next-generation sequencing, and whole-exome sequencing, we describe distinct missense and splice-impacting mutations inPOLA1in five unrelated families presenting with an X-linked syndrome involving intellectual disability, proportionate short stature, microcephaly, and hypogonadism.POLA1encodes the p180 catalytic subunit of DNA polymerase α-primase. A range of replicative impairments could be demonstrated in lymphoblastoid cell lines derived from affected individuals. Our findings describe the presentation of pathogenic mutations in a catalytic component of a B family DNA polymerase member, DNA polymerase α.