Iranian Research Center on Aging, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
Department of Genomic Psychiatry and Behavioral Genomics (DGPBG), Roozbeh Hospital, School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran.
Sci Rep. 2020 Nov 10;10(1):19454. doi: 10.1038/s41598-020-76461-z.
The human X-linked zinc finger MYM-type protein 3 (ZMYM3) contains the longest GA-STR identified across protein-coding gene 5' UTR sequences, at 32-repeats. This exceptionally long GA-STR is located at a complex string of GA-STRs with a human-specific formula across the complex as follows: (GA)8-(GA)4-(GA)6-(GA)32 (ZMYM3-207 ENST00000373998.5). ZMYM3 was previously reported among the top three genes involved in the progression of late-onset Alzheimer's disease. Here we sequenced the ZMYM3 GA-STR complex in 750 human male subjects, consisting of late-onset neurocognitive disorder (NCD) as a clinical entity (n = 268) and matched controls (n = 482). We detected strict monomorphism of the GA-STR complex, except of the exceptionally long STR, which was architecturally skewed in respect of allele distribution between the NCD cases and controls [F (1, 50) = 12.283; p = 0.001]. Moreover, extreme alleles of this STR at 17, 20, 42, and 43 repeats were detected in seven NCD patients and not in the control group (Mid-P exact = 0.0003). A number of these alleles overlapped with alleles previously found in schizophrenia and bipolar disorder patients. In conclusion, we propose selective advantage for the exceptional length of the ZMYM3 GA-STR in human, and its link to a spectrum of diseases in which major cognition impairment is a predominant phenotype.
人类 X 连锁锌指 MYM 型蛋白 3（ZMYM3）在蛋白质编码基因 5'UTR 序列中包含已识别的最长 GA-STR，重复次数为 32 次。这个异常长的 GA-STR 位于一个复杂的 GA-STR 串中，该串在整个复杂结构中具有人类特异性公式，如下所示：（GA）8-（GA）4-（GA）6-（GA）32（ZMYM3-207ENST00000373998.5）。ZMYM3 先前被报道是参与晚发性阿尔茨海默病进展的前三大基因之一。在这里，我们对 750 名男性人类受试者中的 ZMYM3 GA-STR 复合物进行了测序，其中包括作为临床实体的晚发性神经认知障碍（NCD，n=268）和匹配的对照（n=482）。我们发现 GA-STR 复合物除了异常长的 STR 之外严格是单态性的，该 STR 在 NCD 病例和对照组之间的等位基因分布方面在结构上存在偏斜[F（1，50）=12.283；p=0.001]。此外，在 7 名 NCD 患者中检测到该 STR 的极端等位基因，重复数为 17、20、42 和 43，而对照组中未检测到（Mid-Pexact=0.0003）。这些等位基因中有许多与精神分裂症和双相情感障碍患者中发现的等位基因重叠。总之，我们提出 ZMYM3 GA-STR 的异常长度在人类中具有选择性优势，并且与以主要认知障碍为主要表型的一系列疾病有关。
