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Epigenetic remodelling and dysregulation of DLGAP4 is linked with early-onset cerebellar ataxia.

Minocherhomji S, Hansen C, Kim HG, Mang Y, Bak M, Guldberg P, Papadopoulos N, Eiberg H, Doh GD, Møllgård K, Hertz JM, Nielsen JE, Ropers HH, Tümer Z, Tommerup N, Kalscheuer VM, Silahtaroglu A - Hum. Mol. Genet. (2014)

Bottom Line: However, the coordinated epigenetic effects of constitutional chromosomal rearrangements that disrupt genes associated with congenital neurodevelopmental diseases are poorly understood.Disruption of DLGAP4 results in monoallelic hypermethylation of the truncated DLGAP4 promoter CpG island.Our results provide new mechanistic insight into the way a balanced chromosomal rearrangement associated with a neurodevelopmental disorder perturbs allele-specific epigenetic mechanisms at breakpoints leading to the deregulation of the truncated locus.

View Article: PubMed Central - PubMed

Affiliation: Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen N DK-2200, Denmark.

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DLGAP4 is disrupted by the translocation t(8;20)(p12;q11.23) segregating with early-onset, non-progressive, mild cerebellar ataxia. (A) Pedigree of investigated family. (B) Ideograms and translocation chromosomes. (C) FISH mapping of chr20q11.23 breakpoint showing three signals using spanning BAC CTD-2301L1. (D) PCR amplification of disrupted and undisrupted DLGAP4 alleles in t(8;20) carriers and phenotypically normal unrelated (controls) or related (IV.6 and V.6) controls. (E) Representative UCSC genome browser view of the breakpoint region on 20q11.23 showing disruption of DLGAP4, 820 bp downstream (at chr20: 34358534, hg18) of the first untranslated exon. Electropherogram shows base level resolution of the breakpoint on chromosome der20 with a ‘TGG’ deletion (red highlight). (F) Translocation breakpoint on 8p12 (at chr8: 30901056, hg18) disrupts a region dense in repetitive elements. Electropherogram shows the der8 breakpoint region having a ‘CACT’ deletion (red highlight). The cytosine base (blue highlight) at the breakpoint could be part of 8p or 20q. Yellow highlights indicate the sequence adjacent to breakpoints. Illustrations are drawn to scale; curved arrows denote promoter regions of genes.
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DDU337F1: DLGAP4 is disrupted by the translocation t(8;20)(p12;q11.23) segregating with early-onset, non-progressive, mild cerebellar ataxia. (A) Pedigree of investigated family. (B) Ideograms and translocation chromosomes. (C) FISH mapping of chr20q11.23 breakpoint showing three signals using spanning BAC CTD-2301L1. (D) PCR amplification of disrupted and undisrupted DLGAP4 alleles in t(8;20) carriers and phenotypically normal unrelated (controls) or related (IV.6 and V.6) controls. (E) Representative UCSC genome browser view of the breakpoint region on 20q11.23 showing disruption of DLGAP4, 820 bp downstream (at chr20: 34358534, hg18) of the first untranslated exon. Electropherogram shows base level resolution of the breakpoint on chromosome der20 with a ‘TGG’ deletion (red highlight). (F) Translocation breakpoint on 8p12 (at chr8: 30901056, hg18) disrupts a region dense in repetitive elements. Electropherogram shows the der8 breakpoint region having a ‘CACT’ deletion (red highlight). The cytosine base (blue highlight) at the breakpoint could be part of 8p or 20q. Yellow highlights indicate the sequence adjacent to breakpoints. Illustrations are drawn to scale; curved arrows denote promoter regions of genes.

Mentions: The t(8;20)(p12;q11.23) translocation is inherited from both paternal and maternal lineages and co-segregates with full penetrance in all 14 carriers with autosomal dominant early-onset, non-progressive, mild cerebellar ataxia across five generations (6) (Fig. 1A–C). The patients presented with variable phenotypes including gait, ataxia, mild chorea, clumsiness, impaired hand-coordination and tremors, representing the phenotypic plasticity in this neurological disorder (6).Figure 1.


Epigenetic remodelling and dysregulation of DLGAP4 is linked with early-onset cerebellar ataxia.

Minocherhomji S, Hansen C, Kim HG, Mang Y, Bak M, Guldberg P, Papadopoulos N, Eiberg H, Doh GD, Møllgård K, Hertz JM, Nielsen JE, Ropers HH, Tümer Z, Tommerup N, Kalscheuer VM, Silahtaroglu A - Hum. Mol. Genet. (2014)

DLGAP4 is disrupted by the translocation t(8;20)(p12;q11.23) segregating with early-onset, non-progressive, mild cerebellar ataxia. (A) Pedigree of investigated family. (B) Ideograms and translocation chromosomes. (C) FISH mapping of chr20q11.23 breakpoint showing three signals using spanning BAC CTD-2301L1. (D) PCR amplification of disrupted and undisrupted DLGAP4 alleles in t(8;20) carriers and phenotypically normal unrelated (controls) or related (IV.6 and V.6) controls. (E) Representative UCSC genome browser view of the breakpoint region on 20q11.23 showing disruption of DLGAP4, 820 bp downstream (at chr20: 34358534, hg18) of the first untranslated exon. Electropherogram shows base level resolution of the breakpoint on chromosome der20 with a ‘TGG’ deletion (red highlight). (F) Translocation breakpoint on 8p12 (at chr8: 30901056, hg18) disrupts a region dense in repetitive elements. Electropherogram shows the der8 breakpoint region having a ‘CACT’ deletion (red highlight). The cytosine base (blue highlight) at the breakpoint could be part of 8p or 20q. Yellow highlights indicate the sequence adjacent to breakpoints. Illustrations are drawn to scale; curved arrows denote promoter regions of genes.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4222360&req=5

DDU337F1: DLGAP4 is disrupted by the translocation t(8;20)(p12;q11.23) segregating with early-onset, non-progressive, mild cerebellar ataxia. (A) Pedigree of investigated family. (B) Ideograms and translocation chromosomes. (C) FISH mapping of chr20q11.23 breakpoint showing three signals using spanning BAC CTD-2301L1. (D) PCR amplification of disrupted and undisrupted DLGAP4 alleles in t(8;20) carriers and phenotypically normal unrelated (controls) or related (IV.6 and V.6) controls. (E) Representative UCSC genome browser view of the breakpoint region on 20q11.23 showing disruption of DLGAP4, 820 bp downstream (at chr20: 34358534, hg18) of the first untranslated exon. Electropherogram shows base level resolution of the breakpoint on chromosome der20 with a ‘TGG’ deletion (red highlight). (F) Translocation breakpoint on 8p12 (at chr8: 30901056, hg18) disrupts a region dense in repetitive elements. Electropherogram shows the der8 breakpoint region having a ‘CACT’ deletion (red highlight). The cytosine base (blue highlight) at the breakpoint could be part of 8p or 20q. Yellow highlights indicate the sequence adjacent to breakpoints. Illustrations are drawn to scale; curved arrows denote promoter regions of genes.
Mentions: The t(8;20)(p12;q11.23) translocation is inherited from both paternal and maternal lineages and co-segregates with full penetrance in all 14 carriers with autosomal dominant early-onset, non-progressive, mild cerebellar ataxia across five generations (6) (Fig. 1A–C). The patients presented with variable phenotypes including gait, ataxia, mild chorea, clumsiness, impaired hand-coordination and tremors, representing the phenotypic plasticity in this neurological disorder (6).Figure 1.

Bottom Line: However, the coordinated epigenetic effects of constitutional chromosomal rearrangements that disrupt genes associated with congenital neurodevelopmental diseases are poorly understood.Disruption of DLGAP4 results in monoallelic hypermethylation of the truncated DLGAP4 promoter CpG island.Our results provide new mechanistic insight into the way a balanced chromosomal rearrangement associated with a neurodevelopmental disorder perturbs allele-specific epigenetic mechanisms at breakpoints leading to the deregulation of the truncated locus.

View Article: PubMed Central - PubMed

Affiliation: Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen N DK-2200, Denmark.

Show MeSH
Related in: MedlinePlus