title: Exon duplications in the ATP7A gene: frequency and transcriptional behaviour.
abstract: BACKGROUND
  Menkes disease (MD) is an X-linked, fatal neurodegenerative disorder of copper metabolism, caused by mutations in the ATP7A gene. Thirty-three Menkes patients in whom no mutation had been detected with standard diagnostic tools were screened for exon duplications in the ATP7A gene.
  
  
  METHODS
  The ATP7A gene was screened for exon duplications using multiplex ligation-dependent probe amplification (MLPA). The expression level of ATP7A was investigated by real-time PCR and detailed analysis of the ATP7A mRNA was performed by RT-PCR followed by sequencing. In order to investigate whether the identified duplicated fragments originated from a single or from two different X-chromosomes, polymorphic markers located in the duplicated fragments were analyzed.
  
  
  RESULTS
  Partial ATP7A gene duplication was identified in 20 unrelated patients including one patient with Occipital Horn Syndrome (OHS). Duplications in the ATP7A gene are estimated from our material to be the disease causing mutation in 4% of the Menkes disease patients. The duplicated regions consist of between 2 and 15 exons. In at least one of the cases, the duplication was due to an intra-chromosomal event. Characterization of the ATP7A mRNA transcripts in 11 patients revealed that the duplications were organized in tandem, in a head to tail direction. The reading frame was disrupted in all 11 cases. Small amounts of wild-type transcript were found in all patients as a result of exon-skipping events occurring in the duplicated regions. In the OHS patient with a duplication of exon 3 and 4, the duplicated out-of-frame transcript coexists with an almost equally represented wild-type transcript, presumably leading to the milder phenotype.
  
  
  CONCLUSIONS
  In general, patients with duplication of only 2 exons exhibit a milder phenotype as compared to patients with duplication of more than 2 exons. This study provides insight into exon duplications in the ATP7A gene.
authors.affiliation: Center for Applied Human Molecular Genetics, Kennedy Center, Gl, Landevej 7, 2600 Glostrup Denmark.
authors.forename: Mie
authors.initials: M
authors.lastname: Mogensen
authors.forename: Tina
authors.initials: T
authors.lastname: Skjørringe
authors.forename: Hiroko
authors.initials: H
authors.lastname: Kodama
authors.forename: Kenneth
authors.initials: K
authors.lastname: Silver
authors.forename: Nina
authors.initials: N
authors.lastname: Horn
authors.forename: Lisbeth B
authors.initials: LB
authors.lastname: Møller
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics* / Q000378:metabolism*; D000328:Adult; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D002675:Child, Preschool; D000073840:Copper-Transporting ATPases; D003483:Cutis Laxa / Q000235:genetics; D004535:Ehlers-Danlos Syndrome / Q000235:genetics; D005091:Exons / Q000235:genetics*; D005260:Female; D020440:Gene Duplication; D006801:Humans; D008297:Male; D007706:Menkes Kinky Hair Syndrome / Q000235:genetics* / Q000473:pathology; D015336:Molecular Probe Techniques; D060885:Multiplex Polymerase Chain Reaction; D009154:Mutation; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055815:Young Adult
chemical_list: D027682:Cation Transport Proteins; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases
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