Synthetic combinations of missense polymorphic genetic changes underlying Down syndrome susceptibility

Jackson, Rebecca; Nguyen, Mai Linh; Barrett, Angela N.; Tan, Yuan; Choolani, Mahesh; Chen, Ee Sin

doi:10.1007/s00018-016-2276-0

Cited by 12 publications

(8 citation statements)

References 144 publications

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“…[7] Common MTHFR polymorphisms, namely C677T and A1298C, impair MTHFR stability and activity overall leading to hyperhomocysteinemia and reduced SAM production, and have been largely investigated as maternal risk factors for spontaneous abortion and DS risk. [6,7,[16][17][18][19][20][21][22][23][24][25][26][27][28]34] Previous literature meta-analyses support an association between the maternal MTHFR C677T polymorphism and the risk of birth of a child with DS, [23][24][25] but many questions are still unsolved. Particularly, it is becoming evident that combined MTHFR C677T/ A1298C genotypes give rise to more or less stable MTHFR dimers, and that intracellular levels of folate, SAM, and metabolic cofactors regulate MTHFR protein stability and activity, as well as the promoter methylation and expression levels of the MTHFR gene itself, [7,12,28] also the frequency of MTHFR polymorphisms and their combinations varies among different populations, likely as a result of complex gene-nutrient interactions over time that might have favored certain haplotypes.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, both MTHFR C677T and A1298C polymorphisms have been linked to an increased risk of chromosome malsegregation in lymphocytes of mothers of DS children [15] . Following the original study by James and coworkers, [6] several investigators performed case–control studies to evaluate MTHFR C677T and/or A1298C polymorphisms as maternal risk factors for the birth of a child with DS, but the small sample-size of these studies coupled to differences in allele frequencies, lifestyles and dietary habits among different populations, yielded conflicting results [15–22] …”

Section: Introductionmentioning

confidence: 99%

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Association between MTHFR C677T and A1298C gene polymorphisms and maternal risk for Down syndrome

et al. 2022

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Background: Down syndrome (DS) is one of the most common chromosomal abnormalities among live-born babies and one of the best-known intellectual disability disorders in humans. Errors leading to trisomy 21 are primarily arising from defects in chromosomal segregation during maternal meiosis (about 88% of cases), and the focus of many investigations has been to identify maternal risk factors favoring chromosome 21 malsegregation during oogenesis. Maternal polymorphisms of genes required for folate metabolism are the most investigated risk factors for the birth of children with DS. Through this review, we sought to investigate the association of the polymorphisms “C677T” and “A1298C” of the MTHFR gene with maternal risk for DS. Methods: We will use the databases PubMed, Embase, Scopus and Web of Science to search for case-control studies published from 1999 up to September 2021 without language restriction. Results will be presented as relative risks and 95% confidence intervals for dichotomous outcomes and mean differences, or standardized mean differences along with 95% confidence intervals, for continuous outcomes. The all data synthesis will be analyzed on the Review Manager 5.2 version software. Results: This study will be able to clarify all the doubts we seek and that it will be able to provide accurate data that will be able to describe how these polymorphisms can act to increase the predisposition for the birth of children with DS in different populations and under different dietary conditions. Conclusions: This study will clarify the relationship between C677T and A1298C polymorphisms MTHFR gene with increased the maternal risk for Down syndrome. Registration: This systematic review and meta-analysis protocol has been registered on the Prospective Registry of International Systematic Review and Meta-analyses: CRD42021269338.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Association between MTHFR C677T and A1298C gene polymorphisms and maternal risk for Down syndrome

et al. 2022

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“…Proper segregation of chromosomes during cell division is essential for precise inheritance of the genomes and the loss of its fidelity often underlies human diseases, such as hereditary syndromes and cancers [ 1 , 2 , 3 ]. During M-phase, spindle microtubules emanate from the microtubule organization centers at the cell poles to capture the chromosomes at a locus termed centromere.…”

Section: Introductionmentioning

confidence: 99%

GRANT Motif Regulates CENP-A Incorporation and Restricts RNA Polymerase II Accessibility at Centromere

Tan

Chen

2022

Genes

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Precise chromosome segregation is essential for maintaining genomic stability, and its proper execution centers on the centromere, a chromosomal locus that mounts the kinetochore complex to mediate attachment of chromosomes to the spindle microtubules. The location of the centromere is epigenetically determined by a centromere-specific histone H3 variant, CENP-A. Many human cancers exhibit overexpression of CENP-A, which correlates with occurrence of aneuploidy in these malignancies. Centromeric targeting of CENP-A depends on its histone fold, but recent studies showed that the N-terminal tail domain (NTD) also plays essential roles. Here, we investigated implications of NTD in conferring aneuploidy formation when CENP-A is overexpressed in fission yeast. A series of mutant genes progressively lacking one amino acid of the NTD have been constructed for overexpression in wild-type cells using the intermediate strength nmt41 promoter. Constructs hosting disrupted GRANT (Genomic stability-Regulating site within CENP-A N-Terminus) motif in NTD results in growth retardation, aneuploidy, increased localization to the centromere, upregulated RNA polymerase II accessibility and transcriptional derepression of the repressive centromeric chromatin, suggesting that GRANT residues fine-tune centromeric CENP-A incorporation and restrict RNA polymerase II accessibility. This work highlighted the importance of CENP-A NTD, particularly the GRANT motif, in aneuploidy formation of overexpressed CENP-A in fission yeast.

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“…Precise partitioning of chromosomes during mitosis is critical for genomic stability, and the loss of faithfulness during the segregation of genetic and epigenetic information is associated with many human diseases, including cancers and birth defects [1,2]. Chromosome segregation is brought about by the attachment of mitotic spindle microtubules that emanate from centrosomes (or spindle pole bodies) at cell poles to the kinetochores, which are specialized mega-protein complexes assembled onto chromosomal loci called centromeres [3,4].…”

Section: Introductionmentioning

confidence: 99%

N-Terminus Does Not Govern Protein Turnover of Schizosaccharomyces pombe CENP-A

Tan

Zeng

Chen

2020

IJMS

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Centromere integrity underlies an essential framework for precise chromosome segregation and epigenetic inheritance. Although centromeric DNA sequences vary among different organisms, all eukaryotic centromeres comprise a centromere-specific histone H3 variant, centromeric protein A (CENP-A), on which other centromeric proteins assemble into the kinetochore complex. This complex connects chromosomes to mitotic spindle microtubules to ensure accurate partitioning of the genome into daughter cells. Overexpression of CENP-A is associated with many cancers and is correlated with its mistargeting, forming extra-centromeric kinetochore structures. The mislocalization of CENP-A can be counteracted by proteolysis. The amino (N)-terminal domain (NTD) of CENP-A has been implicated in this regulation and shown to be dependent on the proline residues within this domain in Saccharomyces cerevisiae CENP-A, Cse4. We recently identified a proline-rich GRANT motif in the NTD of Schizosaccharomyces pombe CENP-A (SpCENP-A) that regulates the centromeric targeting of CENP-A via binding to the CENP-A chaperone Sim3. Here, we investigated whether the NTD is required to confer SpCENP-A turnover (i.e., counter stability) using various truncation mutants of SpCENP-A. We show that sequential truncation of the NTD did not improve the stability of the protein, indicating that the NTD of SpCENP-A does not drive turnover of the protein. Instead, we reproduced previous observations that heterochromatin integrity is important for SpCENP-A stability, and showed that this occurs in an NTD-independent manner. Cells bearing the null mutant of the histone H3 lysine 9 methyltransferase Clr4 (Δclr4), which have compromised constitutive heterochromatin integrity, showed reductions in the proportion of SpCENP-A in the chromatin-containing insoluble fraction of the cell extract, suggesting that heterochromatin may promote SpCENP-A chromatin incorporation. Thus, a disruption in heterochromatin may result in the delocalization of SpCENP-A from chromatin, thus exposing it to protein turnover. Taken together, we show that the NTD is not required to confer SpCENP-A protein turnover.

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Synthetic combinations of missense polymorphic genetic changes underlying Down syndrome susceptibility

Cited by 12 publications

References 144 publications

Association between MTHFR C677T and A1298C gene polymorphisms and maternal risk for Down syndrome

Association between MTHFR C677T and A1298C gene polymorphisms and maternal risk for Down syndrome

GRANT Motif Regulates CENP-A Incorporation and Restricts RNA Polymerase II Accessibility at Centromere

N-Terminus Does Not Govern Protein Turnover of Schizosaccharomyces pombe CENP-A

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