Disease-only alleles at the extreme ends of the human ZMYM3 exceptionally long 5′ UTR short tandem repeat in bipolar disorder: A pilot study

Alizadeh, Fatemeh; Moharrami, Tamouchin; Mousavi, Negar; Yazarlou, Fatemeh; Bozorgmehr, Ali; Shahsavand, Esmaeil; Delbari, Ahmad; Ohadi, Mina

doi:10.1016/j.jad.2019.03.056

Cited by 12 publications

(18 citation statements)

References 19 publications

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“…Recent findings of a link between the low-frequency alleles at the extreme short and long ends of "exceptionally long" STRs with human disorders [5][6][7] Fig. 8.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously reported that approximately 2% of the human protein-coding genes contain STRs of ≥6 repeats in the critical core promoter region [3]. Preliminary findings indicate that expansion of a number of these STRs may be linked to adaptive evolutionary processes in human, and also endure the burden of certain human disorders such as schizophrenia, bipolar disorder, and Alzheimer's disease [4][5][6][7].…”

Section: Introductionmentioning

confidence: 92%

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Natural Selection at the NHLH2 Core Promoter Exceptionally Long CA-Repeat in Human and Disease-Only Genotypes in Late-Onset Neurocognitive Disorder

Afshar¹,

Adelirad²,

Kowsari³

et al. 2020

Gerontology

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Background: Approximately 2% of the human core promoter short tandem repeats (STRs) reach lengths of ≥6 repeats, which may in part be a result of adaptive evolutionary processes and natural selection. A single-exon transcript of the human nescient helix loop helix 2 (NHLH2) gene is flanked by the longest CA-repeat detected in a human protein-coding gene core promoter (Ensembl transcript ID: ENST00000369506.1). NHLH2 is involved in several biological and pathological pathways, such as motivated exercise, obesity, and diabetes. Methods: The allele and genotype distribution of the NHLH2 CA-repeat were investigated by sequencing in 655 Iranian subjects, consisting of late-onset neurocognitive disorder (NCD) as a clinical entity (n = 290) and matched controls (n = 365). The evolutionary trend of the CA-repeat was also studied across vertebrates. Results: The allele range was between 9 and 25 repeats in the NCD cases, and 12 and 24 repeats in the controls. At the frequency of 0.56, the 21-repeat allele was the predominant allele in the controls. While the 21-repeat was also the predominant allele in the NCD patients, we detected significant decline of the frequency (p < 0.0001) and homozygosity (p < 0.006) of this allele in this group. Furthermore, 12 genotypes were detected across 16 patients (5.5% of the entire NCD sample) and not in the controls (disease-only genotypes; p < 0.0003), consisting of at least one extreme allele. The extreme alleles were at 9, 12, 13, 18, and 19 repeats (extreme short end), and 23, 24, and 25 repeats (extreme long end), and their frequencies ranged between 0.001 and 0.04. The frequency of the 21-repeat allele significantly dropped to 0.09 in the disease-only genotype compartment (p <

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“…Recent findings of a link between the low-frequency alleles at the extreme short and long ends of "exceptionally long" STRs with human disorders [5][6][7] Fig. 8.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 92%

Natural Selection at the NHLH2 Core Promoter Exceptionally Long CA-Repeat in Human and Disease-Only Genotypes in Late-Onset Neurocognitive Disorder

Afshar¹,

Adelirad²,

Kowsari³

et al. 2020

Gerontology

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“…The chi-squared test was used to compare the distribution of each allele between the control and NCD groups. The Mid-P exact test was used for the alleles detected at the extreme ends of the allele distribution curve, which were detected in the NCD patients, and not in the controls in this study and two previous studies of SCZ and BPD 8,9 . Levene's test was used to assess the equality of variances of allelic distribution for the two groups.…”

Section: Discussionmentioning

confidence: 99%

“…We investigated the ZMYM3 GA-STR complex in late-onset NCD as a clinical entity, without differentiating the subtypes of NCD. The advantage of this novel approach was to eliminate the often-ambiguous diagnoses made for the NCD subtypes, which frequently co-occur and overlap in respect of the clinical and pathophysiological manifestations 9,[21][22][23][24][25] .…”

Section: Discussionmentioning

confidence: 99%

“…and the 5′ untranslated region (UTR) 6 . The emerging comparative and functional analyses of a number of the identified STRs support adaptive evolutionary patterns for the expansion of a number of these STRs 3,7 , and the co-occurrence of alleles at the extreme ends of these STRs with major human cognitive disorders, including schizophrenia (SCZ), bipolar disorder (BPD) and late-onset NCD [8][9][10][11][12] .In line with the above findings, recent reports indicate that STR length influences expression quantitative trait loci (eQTL) associations 13 .…”

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confidence: 96%

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

Afshar

Khamse

Alizadeh

et al. 2020

Sci Rep

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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.

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Novel implications of a strictly monomorphic (GCC) repeat in the human PRKACB gene

Khamse

Jafarian

Bozorgmehr

et al. 2021

Sci Rep

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PRKACB (Protein Kinase CAMP-Activated Catalytic Subunit Beta) is predominantly expressed in the brain, and regulation of this gene links to neuroprotective effects against tau and Aβ-induced toxicity. Here we studied a (GCC)-repeat spanning the core promoter and 5′ UTR of this gene in 300 human subjects, consisting of late-onset neurocognitive disorder (NCD) (N = 150) and controls (N = 150). We also implemented several models to study the impact of this repeat on the three-dimensional (3D) structure of DNA. While the PRKACB (GCC)-repeat was strictly monomorphic at 7-repeats, we detected two 7/8 genotypes only in the NCD group. In all examined models, the (GCC)7 and its periodicals had the least range of divergence variation on the 3D structure of DNA in comparison to the 8-repeat periodicals and several hypothetical repeat lengths. A similar inert effect on the 3D structure was not detected in other classes of short tandem repeats (STRs) such as GA and CA repeats. In conclusion, we report monomorphism of a long (GCC)-repeat in the PRKACB gene in human, its inert effect on DNA structure, and enriched divergence in late-onset NCD. This is the first indication of natural selection for a monomorphic (GCC)-repeat, which probably evolved to function as an “epigenetic knob”, without changing the regional DNA structure.

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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

Cited by 12 publications

References 19 publications

Natural Selection at the NHLH2 Core Promoter Exceptionally Long CA-Repeat in Human and Disease-Only Genotypes in Late-Onset Neurocognitive Disorder

Natural Selection at the NHLH2 Core Promoter Exceptionally Long CA-Repeat in Human and Disease-Only Genotypes in Late-Onset Neurocognitive Disorder

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

Novel implications of a strictly monomorphic (GCC) repeat in the human PRKACB gene

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