Department of Genomic Psychiatry and Behavioral Genomics (DGPBG), Roozbeh Hospital, School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran.
Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran.
J Affect Disord. 2019 May 15;251:86-90. doi: 10.1016/j.jad.2019.03.056. Epub 2019 Mar 20.
The X-linked ZMYM3 gene (also known as ZNF261) contains the longest STR, (GA)32, identified in a human protein-coding gene 5'UTR (ENST00000373998.5: ZMYM3-207). This STR reaches maximum length in human, and is located in a complex string of four consecutive GA-STRs with a human-specific formula across the complex. A previous study in Iranian male schizophrenia (SCZ) patients revealed co-occurrence of the extreme short and long alleles of the STR with SCZ. Here we studied the allelic distribution of this STR in bipolar disorder (BD) type I. The interval encompassing the human ZMYM3 STR complex was PCR-amplified and sequenced in 546 male subjects, consisting of 157 BD patients and 389 controls.
We found three alleles at the extreme short (17-repeat) and long (38- and 43-repeat) ends of the allele distribution curve in the BD cases (4.4% of the BD alleles) that were not detected in the controls (Mid p < 0.0001). These alleles overlapped with the extreme disease-only alleles detected previously in the SCZ patients. Domain reconstruction of the GA-STR complex revealed significant structural alteration as a result of various sequence repeats and nucleotide compositions at the inter and intraspecies levels.
The ZMYM3 "exceptionally long" 5' UTR STR findings may alter our perspective of disease pathogenesis in psychiatric disorders, and set an example in which the low frequency alleles at the extreme short and long ends of the human STRs are, at least in part, a result of natural selection against these alleles and their unambiguous link to major human disorders.
X 连锁的 ZMYM3 基因（也称为 ZNF261）包含人类蛋白质编码基因 5'UTR 中鉴定出的最长 STR（GA）32（ENST00000373998.5：ZMYM3-207）。该 STR 在人类中达到最大长度，位于一个复杂的连续四个 GA-STR 字符串中，在整个复合物中具有人类特异性公式。先前在伊朗男性精神分裂症（SCZ）患者中的研究显示，STR 的极端短和长等位基因与 SCZ 同时发生。在这里，我们研究了 I 型双相情感障碍（BD）中该 STR 的等位基因分布。包含人类 ZMYM3 STR 复合物的间隔通过 PCR 扩增并在 546 名男性受试者中进行测序，其中包括 157 名 BD 患者和 389 名对照。
我们在 BD 病例中发现了极端短（17 重复）和长（38-和 43 重复）等位基因分布曲线末端的三个等位基因（BD 等位基因的 4.4%），在对照中未检测到（中位数 p <0.0001）。这些等位基因与之前在 SCZ 患者中检测到的极端疾病等位基因重叠。GA-STR 复合物的结构域重建表明，在种间和种内水平上，各种序列重复和核苷酸组成导致结构发生重大改变。
ZMYM3“异常长”5'UTR STR 发现可能改变我们对精神疾病发病机制的看法，并为我们提供了一个范例，即在人类 STR 的极端短和长端的低频等位基因至少部分是由于自然选择对这些等位基因的排斥及其与主要人类疾病的明确联系所致。
