Complex genomic rearrangements at the PLP1 locus include triplication and quadruplication

PLoS Genet. 2015 Mar 6;11(3):e1005050. doi: 10.1371/journal.pgen.1005050. eCollection 2015 Mar.


Inverted repeats (IRs) can facilitate structural variation as crucibles of genomic rearrangement. Complex duplication-inverted triplication-duplication (DUP-TRP/INV-DUP) rearrangements that contain breakpoint junctions within IRs have been recently associated with both MECP2 duplication syndrome (MIM#300260) and Pelizaeus-Merzbacher disease (PMD, MIM#312080). We investigated 17 unrelated PMD subjects with copy number gains at the PLP1 locus including triplication and quadruplication of specific genomic intervals-16/17 were found to have a DUP-TRP/INV-DUP rearrangement product. An IR distal to PLP1 facilitates DUP-TRP/INV-DUP formation as well as an inversion structural variation found frequently amongst normal individuals. We show that a homology-or homeology-driven replicative mechanism of DNA repair can apparently mediate template switches within stretches of microhomology. Moreover, we provide evidence that quadruplication and potentially higher order amplification of a genomic interval can occur in a manner consistent with rolling circle amplification as predicted by the microhomology-mediated break induced replication (MMBIR) model.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromosome Breakpoints
  • Chromosome Inversion
  • Gene Dosage
  • Gene Duplication*
  • Humans
  • Myelin Proteolipid Protein / genetics*
  • Pelizaeus-Merzbacher Disease / genetics*


  • Myelin Proteolipid Protein
  • PLP1 protein, human