Complex genomic rearrangements at the PLP1 locus include triplication and quadruplication.
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.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
Christine R
CR
Beck
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America; Centro de Pesquisas Rene Rachou- FIOCRUZ, Belo Horizonte, Minas Gerais, Brazil.
Claudia M B
CM
Carvalho
Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, Delaware, United States of America.
Linda
L
Banser
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
Tomasz
T
Gambin
Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, Delaware, United States of America.
Danielle
D
Stubbolo
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
Bo
B
Yuan
Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, Delaware, United States of America.
Karen
K
Sperle
Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, Delaware, United States of America; Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
Suzanne M
SM
McCahan
Department of Pediatrics and Adolescent Medicine, Division of Pediatric Neurology, University Medical Center Göttingen, Georg August University, Göttingen, Germany.
Marco
M
Henneke
Department of Pediatric Neurology, DNA Laboratory, 2nd Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic.
Pavel
P
Seeman
University of Rochester Medical Center, Rochester, New York, United States of America.
James Y
JY
Garbern
Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, Delaware, United States of America; Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America; University of Delaware, Department of Biological Sciences, Newark, Delaware, United States of America.
Grace M
GM
Hobson
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America; Department of Pediatrics and Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States of America; Texas Children's Hospital, Houston, Texas, United States of America.
James R
JR
Lupski
D056905:Chromosome Breakpoints; D007446:Chromosome Inversion; D018628:Gene Dosage; D020440:Gene Duplication; D006801:Humans; D018991:Myelin Proteolipid Protein / Q000235:genetics*; D020371:Pelizaeus-Merzbacher Disease / Q000235:genetics*
D018991:Myelin Proteolipid Protein; C472930:PLP1 protein, human