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

Abstract

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.

Zinc Finger Proteins in Neuro-Related Diseases Progression

“…ZMYM3 contains the longest GA-STR which gives it an advantage in the selective expression of human genes. Alleles of the GA-STR complex were found to be associated with late-onset neurocognitive disorder (NCD), schizophrenia and bipolar disorder ( Alizadeh et al, 2019 ; Afshar et al, 2020 ). ZMYM3 can regulate the transcriptional signal of AD, and severe AD is often accompanied by low level of ZMYM3 expression in the brain nucleus ( Alizadeh et al, 2019 ; Afshar et al, 2020 ).…”

“…Alleles of the GA-STR complex were found to be associated with late-onset neurocognitive disorder (NCD), schizophrenia and bipolar disorder ( Alizadeh et al, 2019 ; Afshar et al, 2020 ). ZMYM3 can regulate the transcriptional signal of AD, and severe AD is often accompanied by low level of ZMYM3 expression in the brain nucleus ( Alizadeh et al, 2019 ; Afshar et al, 2020 ). Cdkn1A-interacting zinc finger protein 1 (CIZ1) can bind to DNA and regulate DNA replication, entering to S phase by inducing the cytoplasmic export of CDKN1A (p21 CIP1), which is a major factor in blocking the onset of S phase ( Dahmcke et al, 2008 ; Liu et al, 2016 ).…”

Natural selection at the RASGEF1C (GGC) repeat in human and divergent genotypes in late-onset neurocognitive disorder.

“…Numerous STRs in the critical core promoter and 5′ untranslated regions (UTRs) are speci c to primates [4][5][6] , and may have a link to the evolution of this order through various mechanisms, such as gene expression and translation regulation. In a number of instances, there are indications of a link between STRs and late-onset neurocognitive disorders (NCDs) in human such as Alzheimer's disease (AD) and Parkinson's disease (PD) [7][8][9] . RASGEF1C (RasGEF Domain Family Member 1C), located on chromosome 5q35.3, contains a (GGC)repeat of 13-repeats, spanning its core promoter and 5′ UTR (RASGEF1C-201 ENST00000361132.9) 10 .…”

Novel biological implication of a strictly monomorphic GCC repeat in the human PRKACB gene

“…Because of their polymorphic nature and plasticity, these elements provide an efficient source of variation at the inter-and intraspecies levels [1][2][3][4][5][6] . Accumulating evidence indicates that certain STRs may be associated with selective advantage in human and other species [7][8][9][10] . Among the exceptionally long STRs spanning the core promoter and 5′ untranslated region (UTR) of human protein-coding genes, the protein kinase cAMP-activated catalytic subunit beta (PRKACB) gene contains one of the longest GCC-repeats, at 7-repeats 5 .…”