Increased Expression of the Multimerin-1 Gene in α-Synuclein Knokout Mice

Chaprov, Kirill; Goloborshcheva, Valeria V; Tarasova, Tatiana; Teterina, E V; Корокин, М. В.; Солдатов, Владислав О.; Pokrovskiy, Mikhail V.; Kucheryanu, V. G.; Morozov, Sergey G.; Овчинников, Р. К.

doi:10.1134/s0012496620050014

Cited by 5 publications

(4 citation statements)

References 12 publications

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“…Both SNPs affected the differential expression of SNCA transcripts and rs3910105 also affected the MMRN1 gene that is adjacent to the SNCA gene. MMRN1 is elastin microfibril interface 4 and is able to carry platelet factor V. A recent study identified that MMRN1 expression was increased in SNCA knockout mice that was attributed to the genetic modification in the SNCA locus [38]. However, our study identified regulatory link between the intronic SNP in SNCA gene and MMRN1 gene expression.…”

Section: Discussioncontrasting

confidence: 49%

Transcript Variants of Genes Involved in Neurodegeneration Are Differentially Regulated by the APOE and MAPT Haplotypes

Kõks

Pfaff

Bubb

et al. 2021

Genes

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Genetic variations at the Apolipoprotein E (ApoE) and microtubule-associated protein tau (MAPT) loci have been implicated in multiple neurogenerative diseases, but their exact molecular mechanisms are unclear. In this study, we performed transcript level linear modelling using the blood whole transcriptome data and genotypes of the 570 subjects in the Parkinson’s Progression Markers Initiative (PPMI) cohort. ApoE, MAPT haplotypes and two SNPs at the SNCA locus (rs356181, rs3910105) were used to detect expression quantitative trait loci eQTLs associated with the transcriptome and differential usage of transcript isoforms. As a result, we identified 151 genes associated with the genotypic variations, 29 cis and 122 trans eQTL positions. Profound effect with genome-wide significance of ApoE e4 haplotype on the expression of TOMM40 transcripts was identified. This finding potentially explains in part the frequently established genetic association with the APOE e4 haplotypes in neurodegenerative diseases. Moreover, MAPT haplotypes had significant differential impact on 23 transcripts from the 17q21.31 and 17q24.1 loci. MAPT haplotypes had also the largest up-regulating (256) and the largest down-regulating (−178) effect sizes measured as β values on two different transcripts from the same gene (LRRC37A2). Intronic SNP in the SNCA gene, rs3910105, differentially induced expression of three SNCA isoforms. In conclusion, this study established clear association between well-known haplotypic variance and transcript specific regulation in the blood. APOE e4 and MAPT H1/H2 haplotypic variants are associated with the expression of several genes related to the neurodegeneration.

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Section: Discussioncontrasting

confidence: 49%

Transcript Variants of Genes Involved in Neurodegeneration Are Differentially Regulated by the APOE and MAPT Haplotypes

Kõks

Pfaff

Bubb

et al. 2021

Genes

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“…Indeed, impaired platelet adhesion and thrombus formation observed in the C57BL/6JOlaHsd substrain was shown to be rescued by recombinant multimerin 1 infusion 53 . Interestingly, multimerin 1 expression is increased in αsyn KO mouse 54 . Other predicted genes in this region, such as Gm43864, Gm43867, and Gm18838, could also contribute to the findings attributed to the Rab27 DKO phenotype.…”

Section: Discussionmentioning

confidence: 94%

Deletion in chromosome 6 spanning alpha-synuclein and multimerin1 loci in the Rab27a/b double knockout mouse

Pattanayak

Underwood

Crowley

et al. 2022

Sci Rep

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We report an incidental 358.5 kb deletion spanning the region encoding for alpha-synuclein (αsyn) and multimerin1 (Mmrn1) in the Rab27a/Rab27b double knockout (DKO) mouse line previously developed by Tolmachova and colleagues in 2007. Western blot and RT-PCR studies revealed lack of αsyn expression at either the mRNA or protein level in Rab27a/b DKO mice. PCR of genomic DNA from Rab27a/b DKO mice demonstrated at least partial deletion of the Snca locus using primers targeted to exon 4 and exon 6. Most genes located in proximity to the Snca locus, including Atoh1, Atoh2, Gm5570, Gm4410, Gm43894, and Grid2, were shown not to be deleted by PCR except for Mmrn1. Using whole genomic sequencing, the complete deletion was mapped to chromosome 6 (60,678,870–61,037,354), a slightly smaller deletion region than that previously reported in the C57BL/6J substrain maintained by Envigo. Electron microscopy of cortex from these mice demonstrates abnormally enlarged synaptic terminals with reduced synaptic vesicle density, suggesting potential interplay between Rab27 isoforms and αsyn, which are all highly expressed at the synaptic terminal. Given this deletion involving several genes, the Rab27a/b DKO mouse line should be used with caution or with appropriate back-crossing to other C57BL/6J mouse substrain lines without this deletion.

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“…Both SNPs affected the differential expression of SNCA transcripts and rs3910105 also affected the MMRN1 gene that is adjacent to the SNCA gene. MMRN1 is elastin microfibril interface 4 and is able to carry platelet factor V. A recent study identified that MMRN1 expression was increased in SNCA knockout mice that was attributed to the genetic modification in the SNCA locus 36 . However, our study identified regulatory link between the intronic SNP in SNCA gene and MMRN1 gene expression.…”

Section: Discussionmentioning

confidence: 99%

Transcript Variants of Genes Involved in Neurodegeneration Are Differentially Regulated by the Apoe and Mapt Haplotypes

Kõks

Pfaff

Bubb

et al. 2021

Preprint

View full text Add to dashboard Cite

Genetic variations at the Apolipoprotein E (ApoE) and microtubule-associated protein tau (MAPT) loci have been implicated in multiple neurogenerative diseases, but their exact molecular mechanisms are unclear. In this study we performed transcript level linear modelling using the blood whole transcriptome data and genotypes of the 570 subjects in the Parkinson’s progression markers initiative (PPMI) cohort. ApoE, MAPT haplotypes and two SNPs at the SNCA locus (rs356181, rs3910105) were used to detect expression quantitative trait loci eQTLs associated with the transcriptome and differential usage of transcript isoforms. As a result, we identified 151 genes associated with the genotypic variations, 29 cis and 122 trans eQTL positions. Profound effect with genome-wide significance of ApoE e4 haplotype on the expression of TOMM40 transcripts was identified. This finding potentially explain in part the frequently established genetic association with the APOE e4 haplotypes in neurodegenerative diseases. Moreover, MAPT haplotypes had significant differential impact on 23 transcripts from the 17q21.31 and 17q24.1 loci. MAPT haplotypes had also the largest (256) and smallest (-178) effect sizes measured as beta values on two different transcripts from the same gene (LRRC37A2). Intronic SNP in the SNCA gene, rs3910105, differentially induces expression of three SNCA isoforms. In conclusion, this study established clear association between well-known haplotypic variance and transcript specific regulation in the blood. APOE e4 and MAPT H1/H2 haplotypic variants are associated with the expression of several genes related to the neurodegeneration.

show abstract

Increased Expression of the Multimerin-1 Gene in α-Synuclein Knokout Mice

Cited by 5 publications

References 12 publications

Transcript Variants of Genes Involved in Neurodegeneration Are Differentially Regulated by the APOE and MAPT Haplotypes

Transcript Variants of Genes Involved in Neurodegeneration Are Differentially Regulated by the APOE and MAPT Haplotypes

Deletion in chromosome 6 spanning alpha-synuclein and multimerin1 loci in the Rab27a/b double knockout mouse

Transcript Variants of Genes Involved in Neurodegeneration Are Differentially Regulated by the Apoe and Mapt Haplotypes

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