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Disease-Only Alleles at the Extreme Ends of the Human Zmym3 Exceptionally Long 5′ Utr Short Tandem Repeat in Bipolar Disorder: A Pilot Study Publisher Pubmed



Alizadeh F1 ; Moharrami T2 ; Mousavi N3 ; Yazarlou F2 ; Bozorgmehr A4 ; Shahsavand E1 ; Delbari A5 ; Ohadi M5
Authors
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Authors Affiliations
  1. 1. Department of Genomic Psychiatry and Behavioral Genomics (DGPBG), Roozbeh Hospital, School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran
  2. 2. Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran
  3. 3. Department of Biology, Parand Branch, Islamic Azad University, Parand, Iran
  4. 4. Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
  5. 5. Iranian Research Center on Aging, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran

Source: Journal of Affective Disorders Published:2019


Abstract

Objective: 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. Results: 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. Conclusion: 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. © 2019
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