Causes and Consequences of Genome Instability in Psychiatric and Neurodegenerative Diseases

Iourov, Ivan Y.; Vorsanova, Svetlana G.; Куринная, О С; Zelenova, Maria A; Vasin, Kirill S.; Yurov, Yuri B.

doi:10.1134/s0026893321010155

Cited by 15 publications

(20 citation statements)

References 118 publications

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“…Moreover, dynamic nature of somatic chromosomal mosaicism leads to the involvement in pathogenetic and ontogenetic processes [ 7 , 36 , 37 ]. These processes are further involved in intercellular genetic (genomic) diversity [ 35 , 38 , 39 ], early-onset brain diseases [ 7 , 10 , 28 , 40 , 41 ], late-onset brain diseases [ 34 , 42 – 46 ], behavior [ 47 ], and aging [ 43 , 48 – 51 ]. Therefore, the analysis of KSM in the context of brain diseases seems to be required.…”

Section: Discussionmentioning

confidence: 99%

Klinefelter syndrome mosaicism in boys with neurodevelopmental disorders: a cohort study and an extension of the hypothesis

Demidova

Kolotii

et al. 2022

Mol Cytogenet

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Background Klinefelter syndrome is a common chromosomal (aneuploidy) disorder associated with an extra X chromosome in males. Regardless of numerous studies dedicated to somatic gonosomal mosaicism, Klinefelter syndrome mosaicism (KSM) has not been systematically addressed in clinical cohorts. Here, we report on the evaluation of KSM in a large cohort of boys with neurodevelopmental disorders. Furthermore, these data have been used for an extension of the hypothesis, which we have recently proposed in a report on Turner’s syndrome mosaicism in girls with neurodevelopmental disorders. Results Klinefelter syndrome-associated karyotypes were revealed in 49 (1.1%) of 4535 boys. Twenty one boys (0.5%) were non-mosaic 47,XXY individuals. KSM was found in 28 cases (0.6%) and manifested as mosaic aneuploidy (50,XXXXXY; 49,XXXXY; 48,XXXY; 48,XXYY; 47,XXY; and 45,X were detected in addition to 47,XXY/46,XY) and mosaic supernumerary marker chromosomes derived from chromosome X (ring chromosomes X and rearranged chromosomes X). It is noteworthy that KSM was concomitant with Rett-syndrome-like phenotypes caused by MECP2 mutations in 5 boys (0.1%). Conclusion Our study provides data on the occurrence of KSM in neurodevelopmental disorders among males. Accordingly, it is proposed that KSM may be a possible element of pathogenic cascades in psychiatric and neurodegenerative diseases. These observations allowed us to extend the hypothesis proposed in our previous report on the contribution of somatic gonosomal mosaicism (Turner’s syndrome mosaicism) to the etiology of neurodevelopmental disorders. Thus, it seems to be important to monitor KSM (a possible risk factor or a biomarker for adult-onset multifactorial brain diseases) and analysis of neuromarkers for aging in individuals with Klinefelter syndrome. Cases of two or more supernumerary chromosomes X were all associated with KSM. Finally, Rett syndrome-like phenotypes associated with KSM appear to be more common in males with neurodevelopmental disorders than previously recognized.

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Section: Discussionmentioning

confidence: 99%

Klinefelter syndrome mosaicism in boys with neurodevelopmental disorders: a cohort study and an extension of the hypothesis

Demidova

Kolotii

et al. 2022

Mol Cytogenet

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“…When transformed into an appreciable population, cells affected by CIN/somatic mosaicism are able to become a source for morbidity and aging [28][29][30]. Moreover, alterations to a number of molecular/cellular pathways (DNA damage response; RNA somatic gene recombination; mTOR, PI3K-Akt, p53, PTEN, MAPK) predispose to CIN/mosaic aneuploidy in the diseased and aged brain [31][32][33]. To highlight the contribution of CIN to normal and pathological brain aging, it seems important to address aging-associated diseases characterized by brain malfunction (e.g., neurodegeneration) and brain-specific CIN.…”

Section: Cin In the Human Brain: An Ontogenetic Viewmentioning

confidence: 99%

“…During the last two decades, an appreciable amount of data on chromosomal variations (aneuploidy) and CIN directly affecting the brain was provided. Currently, it is suggested that several neurodevelopmental, psychiatric and neurodegenerative disorders may be associated with CIN and somatic chromosomal mosaicism confined to the brain or even to specific brain areas [12,14,16,[18][19][20]33,34]. Brain tissue-specific chromosomal mosaicism and CIN are detectable in a significant proportion of cases of common brain diseases, including schizophrenia, autism/intellectual disability and Alzheimer's disease [7,18,30,33].…”

Section: Cin In the Diseased Brain: An Aging Perspectivementioning

confidence: 99%

“…Currently, it is suggested that several neurodevelopmental, psychiatric and neurodegenerative disorders may be associated with CIN and somatic chromosomal mosaicism confined to the brain or even to specific brain areas [12,14,16,[18][19][20]33,34]. Brain tissue-specific chromosomal mosaicism and CIN are detectable in a significant proportion of cases of common brain diseases, including schizophrenia, autism/intellectual disability and Alzheimer's disease [7,18,30,33]. However, CIN is a significantly more prominent biomarker of neurodegeneration (neurodegenerative diseases) when comparing intercellular chromosomal or (cyto)genomic variations between different types of brain disorders with a special emphasis on brain aging [12][13][14][15][16]34,35].…”

Section: Cin In the Diseased Brain: An Aging Perspectivementioning

confidence: 99%

“…Unfortunately, there are few studies dedicated to analyzing brain-specific CIN in other neurodegenerative conditions than Alzheimer's disease. Still, genetic and (cyto)genomic analyses of the neurodegenerating brain have connected mutations in genes involved in safeguarding genome stability, CIN and molecular pathways in neurodegenerative diseases [33]. Similarly to Alzheimer's disease [40,44], mitotic dysfunction and cell cycle errors are common features of neurodegenerative diseases, as a whole [56].…”

Section: Cin In the Diseased Brain: An Aging Perspectivementioning

confidence: 99%

See 2 more Smart Citations

Chromosome Instability, Aging and Brain Diseases

Iourov

Yurov

Vorsanova

et al. 2021

Cells

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Chromosome instability (CIN) has been repeatedly associated with aging and progeroid phenotypes. Moreover, brain-specific CIN seems to be an important element of pathogenic cascades leading to neurodegeneration in late adulthood. Alternatively, CIN and aneuploidy (chromosomal loss/gain) syndromes exhibit accelerated aging phenotypes. Molecularly, cellular senescence, which seems to be mediated by CIN and aneuploidy, is likely to contribute to brain aging in health and disease. However, there is no consensus about the occurrence of CIN in the aging brain. As a result, the role of CIN/somatic aneuploidy in normal and pathological brain aging is a matter of debate. Still, taking into account the effects of CIN on cellular homeostasis, the possibility of involvement in brain aging is highly likely. More importantly, the CIN contribution to neuronal cell death may be responsible for neurodegeneration and the aging-related deterioration of the brain. The loss of CIN-affected neurons probably underlies the contradiction between reports addressing ontogenetic changes of karyotypes within the aged brain. In future studies, the combination of single-cell visualization and whole-genome techniques with systems biology methods would certainly define the intrinsic role of CIN in the aging of the normal and diseased brain.

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FISHing for Chromosome Instability and Aneuploidy in the Alzheimer’s Disease Brain

Yurov

Vorsanova

Iourov

2022

Methods in Molecular Biology

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Causes and Consequences of Genome Instability in Psychiatric and Neurodegenerative Diseases

Cited by 15 publications

References 118 publications

Klinefelter syndrome mosaicism in boys with neurodevelopmental disorders: a cohort study and an extension of the hypothesis

Klinefelter syndrome mosaicism in boys with neurodevelopmental disorders: a cohort study and an extension of the hypothesis

Chromosome Instability, Aging and Brain Diseases

FISHing for Chromosome Instability and Aneuploidy in the Alzheimer’s Disease Brain

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