title: Functional copper transport explains neurologic sparing in occipital horn syndrome.
abstract: OBJECTIVE
  A range of neurologic morbidity characterizes childhood-onset copper transport defects, including severe Menkes disease and milder occipital horn syndrome. Both phenotypes are caused by mutations in ATP7A, which encodes a copper-transporting adenosine triphosphatase, although defects causing occipital horn syndrome are rarely reported and nearly always involve exon-skipping (six of eight prior reports). Our objective was to characterize a novel occipital horn syndrome mutation (N1304S) not associated with aberrant splicing and to determine whether functional copper transport was associated with this allele.
  
  
  METHODS
  We studied two brothers with typical occipital horn syndrome and used yeast complementation and timed growth assays, exploiting a Saccharomyces cerevisiae mutant strain, to assess in vitro N1304S copper transport.
  
  
  RESULTS
  We documented that N1304S has approximately 33% residual copper transport, a result not inconsistent with a similar patient we reported with an exon-skipping mutation whose cells showed correctly spliced mRNA transcripts 36% of normal.
  
  
  CONCLUSIONS
  These patients' mild neurologic phenotypes, together with our yeast complementation and growth experiments, imply that N1304S does not completely block copper transport to the developing brain early in life. The findings suggest that neurologic sparing in untreated occipital horn syndrome is associated with approximately 30% residual functional activity of ATP7A.
authors.affiliation: Unit on Pediatric Genetics, Laboratory of Clinical Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1832, USA.
authors.forename: Jingrong
authors.initials: J
authors.lastname: Tang
authors.forename: Stephen
authors.initials: S
authors.lastname: Robertson
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Lem
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Godwin
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Kaler
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics; D001692:Biological Transport / Q000235:genetics; D001842:Bone and Bones / Q000000981:diagnostic imaging; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D002648:Child; D003300:Copper / Q000378:metabolism*; D000073840:Copper-Transporting ATPases; D004252:DNA Mutational Analysis; D005816:Genetic Complementation Test; D006801:Humans; D008297:Male; D007706:Menkes Kinky Hair Syndrome / Q000235:genetics / Q000378:metabolism*; D009778:Occipital Lobe / Q000002:abnormalities* / Q000378:metabolism; D011859:Radiography; D013577:Syndrome; D001745:Urinary Bladder Diseases / Q000000981:diagnostic imaging; D015003:Yeasts / Q000235:genetics / Q000254:growth & development
chemical_list: D027682:Cation Transport Proteins; D003300:Copper; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases