A nonconservative amino acid change in the UPF3B gene in a patient with schizophrenia.
A nonconservative amino acid change in the UPF3B gene in a patient with schizophrenia.
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精神分裂症患者 UPF3B 基因中的非保守氨基酸变化。
DOI：
10.1097/ypg.0b013e32834accbe
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发表时间：
2012
影响因子：
0.9
通讯作者：
A. McQuillin
中科院分区：
文献类型：
--
作者：
P. Szyszka;Sally Sharp;A. Dedman;H. Gurling;A. McQuillin
中枢神经系统表达的 UPF3B 基因的外显子 7 中的两个移码突变已被发现导致 FG 或 Opitz-Kaveggia 综合征 (OMIM 305450) 和智力障碍 (Tarpey 等人，2007)。在儿童期发病的精神分裂症病例和患有自闭症的亲戚中也发现了突变（Addington 等，2010）。该基因的其他突变还发现于精神发育迟滞和自闭症患者（Laumonnier 等，2010）、非综合征性精神发育迟滞和 Lujan-Fryns 综合征（OMIM 309520）（Tarpey 等，2007）。 UPF3B 蛋白是无义介导的 mRNA 衰变复合体的一部分，可能影响中枢神经系统细胞中多个基因或其亚型的 mRNA 表达和降解的调节（Tarpey 等，2007；Laumonnier 等，2010）。在这项研究中，我们在 630 名精神分裂症志愿者和 625 名超常对照样本中筛选了 UPF3B 外显子 7 的进一步突变。样本收集和确定标准已在之前描述过（Datta 等，2010）。使用高分辨率熔解 (HRM) 方法和 Sensimix HRM 试剂（Bioline，伦敦，英国）进行突变筛选，然后对显示不同熔解模式的 HRM 产物进行测序。大多数病例和对照聚集成一组相似的熔化曲线。然而，1 个病例和 1 个对照样品的熔化曲线异常。序列分析显示每个样品都有不同的单核苷酸变化。在一名精神分裂症患者中，观察到染色体 X 位置 118 975 082（hg19 组装；GenBank 登录号 NM_080632.2 c.764 G > A）处的 C 至 T 核苷酸替换，并预测会导致 UPF3B（Uniprot 登录号）位置 255 (R255L) 处的精氨酸氨基酸替换为亮氨酸Q9BZI7）。在对照个体中，在染色体 X 位置 118 975 179（hg19 组装；GenBank 登录号 NM_080632.2 c.667 A > G）处观察到错义 T 到 C 核苷酸替换。预计这会导致 UPF3B（Uniprot 登录号 Q9BZI7）的第 223 位（I223V）异亮氨酸被缬氨酸取代。携带这些替换的两个受试者都是女性。使用 PolyPhen-2 对这些取代进行的生物信息分析 (http://genics.bwh.harvard.edu/pph2/index.shtml) 显示对照个体中的 I223V 氨基酸变化可能是“良性”的（HumDiv 评分 0.181；敏感性 0.91，特异性 0.83）。相比之下，在精神分裂症患者中观察到的 R255L 替代预计“可能具有损害性”（HumDiv 评分 0.981；敏感性 0.69，特异性 0.94）。对 1000 个基因组计划测序数据（2010 年 11 月发布）检查这些变化的发生情况发现，一名来自肯尼亚卢希亚 (NA19429) 的男子在 X 染色体位置 119 975 082 处含有 C/T 变化，导致 R255L 氨基酸取代，表明这种变化也可能是良性的。本文和文献中的结果表明，UPF3B 的突变可能在导致罕见的精神分裂症病例中发挥作用。
Two frameshift mutations in exon 7 of the central nervous system expressed UPF3B gene have been found causing FG or Opitz–Kaveggia syndrome (OMIM 305450) and intellectual disability (Tarpey et al., 2007). Mutations have also been found in a case of childhood onset schizophrenia and in a relative with autism (Addington et al., 2010). Other mutations in the gene were found in individuals with mental retardation and autism (Laumonnier et al., 2010), nonsyndromic mental retardation and Lujan–Fryns syndrome (OMIM 309520) (Tarpey et al., 2007). The UPF3B protein is part of the nonsensemediated mRNA decay complex and may affect regulation of the expression and degradation of mRNAs of multiple genes or their isoforms in central nervous system cells (Tarpey et al., 2007; Laumonnier et al., 2010). In this study, we screened exon 7 of UPF3B for further mutations in a sample of 630 volunteers with schizophrenia and 625 supernormal controls. Sample collection and ascertainment criteria have been described previously (Datta et al., 2010). Mutation screening was performed using a high-resolution melting (HRM) method with Sensimix HRM reagents (Bioline, London, UK) followed by sequencing of HRM products showing different melting patterns. Most of the cases and controls clustered into one group of similar melting profiles. However, one case and one control sample had abnormal melting profiles. Sequence analysis showed different single-nucleotide changes for each of the samples. In a patient with schizophrenia, a C to T nucleotide substitution at chromosome X position 118 975 082 (hg19 assembly; GenBank accession no. NM_080632.2 c.764 G > A) was observed and was predicted to result in an amino acid substitution of arginine to leucine at position 255 (R255L) of UPF3B (Uniprot accession number Q9BZI7). In the control individual, a missense T to C nucleotide substitution at chromosome X position 118 975 179 (hg19 assembly; GenBank accession no. NM_080632.2 c.667 A > G) was observed. This was predicted to result in an amino acid substitution of isoleucine with valine at the position 223 (I223V) of UPF3B (Uniprot accession number Q9BZI7). Both of the subjects harbouring these substitutions were women. Bioinformatic analysis of these substitutions using PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/index.shtml) revealed that the I223V amino acid change in the control individual was likely to be ‘benign’ (HumDiv score 0.181; sensitivity 0.91, specificity 0.83). In contrast, the R255L substitution observed in the patient suffering from schizophrenia was predicted to be ‘probably damaging’ (HumDiv score 0.981; sensitivity 0.69, specificity 0.94). Examination of the 1000 genomes project sequencing data (November 2010 release) for the occurrence of these changes revealed that one man from Luhya, Kenya (NA19429) contained the C/T change at chromosome X position 119 975 082 leading to the R255L amino acid substitution suggesting that this change might also be benign. The results presented here and from the literature suggest that mutations in UPF3B may have a role in causing rare cases of schizophrenia.