Evolving evidence on a link between the ZMYM3 exceptionally long GA-STR and human cognition

• Published in: Scientific reports Vol. 10; no. 1; p. 19454
• Main Authors: Afshar, H., Khamse, S., Alizadeh, F., Delbari, A., Najafipour, R., Bozorgmehr, A., Khazaei, M., Adelirad, F., Alizadeh, A., Kowsari, A., Ohadi, M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.11.2020; Nature Publishing Group
• Subjects: 5' Untranslated Regions; 631/181; 631/208; 631/337; 631/378; Aged; Aged, 80 and over; Alleles; Alzheimer's disease; Base Sequence; Bipolar disorder; Cognition; Cognition & reasoning; Dinucleotide Repeats - genetics; Gene Frequency; Genes; Genetic Predisposition to Disease - genetics; Genomics; Genotype; Human subjects; Humanities and Social Sciences; Humans; Male; Mental disorders; Microsatellite Repeats - genetics; Middle Aged; multidisciplinary; Neural coding; Neurocognitive Disorders - diagnostic imaging; Neurocognitive Disorders - genetics; Neurocognitive Disorders - psychology; Neurodegenerative diseases; Nuclear Proteins - genetics; Phenotypes; Proteins; Research centers; Schizophrenia; Science; Science (multidisciplinary); Short tandem repeats; Tomography, X-Ray Computed; Zinc finger proteins
• ISSN: 2045-2322; 2045-2322
• 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.