PMID- 27854212
OWN - NLM
STAT- MEDLINE
DCOM- 20180315
LR  - 20180315
IS  - 2214-3599 (Print)
VI  - 3
IP  - 2
DP  - 2016 May 27
TI  - Non Random Distribution of DMD Deletion Breakpoints and Implication of Double 
      Strand Breaks Repair and Replication Error Repair Mechanisms.
PG  - 227-245
AB  - BACKGROUND: Dystrophinopathies are mostly caused by copy number variations, 
      especially deletions, in the dystrophin gene (DMD). Despite the large size of the 
      gene, deletions do not occur randomly but mainly in two hot spots, the main one 
      involving exons 45 to 55. The underlying mechanisms are complex and implicate two 
      main mechanisms: Non-homologous end joining (NHEJ) and micro-homology mediated 
      replication-dependent recombination (MMRDR). OBJECTIVE: Our goals were to assess 
      the distribution of intronic breakpoints (BPs) in the genomic sequence of the 
      main hot spot of deletions within DMD gene and to search for specific sequences 
      at or near to BPs that might promote BP occurrence or be associated with DNA 
      break repair. METHODS: Using comparative genomic hybridization microarray, 57 
      deletions within the intron 44 to 55 region were mapped. Moreover, 21 junction 
      fragments were sequenced to search for specific sequences. RESULTS: Non-randomly 
      distributed BPs were found in introns 44, 47, 48, 49 and 53 and 50% of BPs 
      clustered within genomic regions of less than 700bp. Repeated elements (REs), 
      known to promote gene rearrangement via several mechanisms, were present in the 
      vicinity of 90% of clustered BPs and less frequently (72%) close to scattered 
      BPs, illustrating the important role of such elements in the occurrence of DMD 
      deletions. Palindromic and TTTAAA sequences, which also promote DNA instability, 
      were identified at fragment junctions in 20% and 5% of cases, respectively. 
      Micro-homologies (76%) and insertions or deletions of small sequences were 
      frequently found at BP junctions. CONCLUSIONS: Our results illustrate, in a large 
      series of patients, the important role of RE and other genomic features in DNA 
      breaks, and the involvement of different mechanisms in DMD gene deletions: Mainly 
      replication error repair mechanisms, but also NHEJ and potentially aberrant 
      firing of replication origins. A combination of these mechanisms may also be 
      possible.
FAU - Marey, Isabelle
AU  - Marey I
AD  - Service de Biochimie et Genetique Moleculaire, HUPC Hopital Cochin, Paris, 
      France.
FAU - Ben Yaou, Rabah
AU  - Ben Yaou R
AD  - UPMC-Paris 6, UM 76, INSERM, U974, CNRS, UMR 7215, Center of Research in Myology, 
      Institut de Myologie, Paris, France.
AD  - AP-HP, Groupe Hospitalier Pitie-Salpetriere, Centre de Reference de Pathologie 
      Neuromusculaire Paris-Est, Paris, France.
FAU - Deburgrave, Nathalie
AU  - Deburgrave N
AD  - Service de Biochimie et Genetique Moleculaire, HUPC Hopital Cochin, Paris, 
      France.
FAU - Vasson, Aurelie
AU  - Vasson A
AD  - Service de Biochimie et Genetique Moleculaire, HUPC Hopital Cochin, Paris, 
      France.
FAU - Nectoux, Juliette
AU  - Nectoux J
AD  - Service de Biochimie et Genetique Moleculaire, HUPC Hopital Cochin, Paris, 
      France.
AD  - INSERM, U1016, Institut Cochin, CNRS UMR8104, Universite Paris Descartes, Paris, 
      France.
FAU - Leturcq, France
AU  - Leturcq F
AD  - Service de Biochimie et Genetique Moleculaire, HUPC Hopital Cochin, Paris, 
      France.
AD  - UPMC-Paris 6, UM 76, INSERM, U974, CNRS, UMR 7215, Center of Research in Myology, 
      Institut de Myologie, Paris, France.
FAU - Eymard, Bruno
AU  - Eymard B
AD  - AP-HP, Groupe Hospitalier Pitie-Salpetriere, Centre de Reference de Pathologie 
      Neuromusculaire Paris-Est, Paris, France.
FAU - Laforet, Pascal
AU  - Laforet P
AD  - AP-HP, Groupe Hospitalier Pitie-Salpetriere, Centre de Reference de Pathologie 
      Neuromusculaire Paris-Est, Paris, France.
FAU - Behin, Anthony
AU  - Behin A
AD  - AP-HP, Groupe Hospitalier Pitie-Salpetriere, Centre de Reference de Pathologie 
      Neuromusculaire Paris-Est, Paris, France.
FAU - Stojkovic, Tanya
AU  - Stojkovic T
AD  - AP-HP, Groupe Hospitalier Pitie-Salpetriere, Centre de Reference de Pathologie 
      Neuromusculaire Paris-Est, Paris, France.
FAU - Mayer, Michele
AU  - Mayer M
AD  - AP-HP, Hopital Armand TROUSSEAU, Centre de reference de pathologie 
      neuromusculaire Paris-Est, Paris, France.
FAU - Tiffreau, Vincent
AU  - Tiffreau V
AD  - Universite de Lille 2, EA 4488, Centre de reference des maladies neuromusculaires 
      du CHRU de Lille, Service de medecine physique et readaptation, Hopital 
      Swynghedauw, Lille, France.
FAU - Desguerre, Isabelle
AU  - Desguerre I
AD  - AP-HP, Hopital Necker-Enfants Malades, Service de Neuropediatrie, Centre de 
      reference de pathologie neuromusculaires Garches-Necker-Mondor-Hendaye, Paris, 
      France.
FAU - Boyer, Francois Constant
AU  - Boyer FC
AD  - Service de Medecine Physique et Readaptation, Centre de reference de pathologie 
      neuromusculaires, Hopital Sebastopol, CHU de Reims, Reims, France.
FAU - Nadaj-Pakleza, Aleksandra
AU  - Nadaj-Pakleza A
AD  - Service de neurologie, Centre de reference de pathologie neuromusculaires Pays de 
      Loire, Hopital Larrey, CHU d'Angers, Angers, France.
FAU - Ferrer, Xavier
AU  - Ferrer X
AD  - Service de neurologie, Centre de reference de pathologie neuromusculaires 
      Aquitaine, Hopital Pellegrin, CHU de Bordeaux, Bordeaux, France.
FAU - Wahbi, Karim
AU  - Wahbi K
AD  - APHP, service de cardiologie, Hopital Cochin, Paris, France.
FAU - Becane, Henri-Marc
AU  - Becane HM
AD  - AP-HP, Groupe Hospitalier Pitie-Salpetriere, Centre de Reference de Pathologie 
      Neuromusculaire Paris-Est, Paris, France.
FAU - Claustres, Mireille
AU  - Claustres M
AD  - CHRU Montpellier, Laboratoire de Genetique moleculaire, Montpellier, France.
AD  - Universite de Montpellier, Laboratoire de Genetique de Maladies rares, EA 7402, 
      Montpellier, France.
FAU - Chelly, Jamel
AU  - Chelly J
AD  - Service de Biochimie et Genetique Moleculaire, HUPC Hopital Cochin, Paris, 
      France.
AD  - INSERM, U1016, Institut Cochin, CNRS UMR8104, Universite Paris Descartes, Paris, 
      France.
FAU - Cossee, Mireille
AU  - Cossee M
AD  - CHRU Montpellier, Laboratoire de Genetique moleculaire, Montpellier, France.
AD  - Universite de Montpellier, Laboratoire de Genetique de Maladies rares, EA 7402, 
      Montpellier, France.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Netherlands
TA  - J Neuromuscul Dis
JT  - Journal of neuromuscular diseases
JID - 101649948
RN  - 0 (DMD protein, human)
RN  - 0 (Dystrophin)
SB  - IM
MH  - Comparative Genomic Hybridization
MH  - DNA Breaks, Double-Stranded
MH  - DNA Copy Number Variations/*genetics
MH  - *DNA End-Joining Repair
MH  - DNA Repair
MH  - DNA Replication
MH  - Dystrophin/*genetics
MH  - Humans
MH  - Introns
MH  - Male
MH  - Muscular Dystrophy, Duchenne/*genetics
MH  - *Recombinational DNA Repair
MH  - Sequence Deletion
OTO - NOTNLM
OT  - DMD gene
OT  - deletion breakpoints
OT  - double strand break repair
OT  - replication error repair mechanisms
EDAT- 2016/11/18 06:00
MHDA- 2018/03/16 06:00
CRDT- 2016/11/18 06:00
PHST- 2016/11/18 06:00 [entrez]
PHST- 2016/11/18 06:00 [pubmed]
PHST- 2018/03/16 06:00 [medline]
AID - JND150134 [pii]
AID - 10.3233/JND-150134 [doi]
PST - ppublish
SO  - J Neuromuscul Dis. 2016 May 27;3(2):227-245. doi: 10.3233/JND-150134.