title: Differences in ATP7A gene expression underlie intrafamilial variability in Menkes disease/occipital horn syndrome.
abstract: BACKGROUND
  Pronounced intrafamilial variability is unusual in Menkes disease and its variants. We report two unrelated families featuring affected members with unusually disparate clinical and biochemical phenotypes and explore the underlying molecular mechanisms.
  
  
  METHODS
  We measured biochemical markers of impaired copper transport in five patients from two unrelated families and used RNase protection, quantitative reverse transcription (RT)-PCR, Western blot analysis and yeast complementation studies to characterise two ATP7A missense mutations, A1362D and S637L.
  
  
  RESULTS
  In two brothers (family A) with A1362D, RNase protection and Western blot analyses revealed higher amounts of ATP7A transcript and protein in the older, mildly affected patient, who also had a higher plasma copper level and lower cerebrospinal fluid dihydroxyphenylalanine : dihydroxyphenylglycol ratio. These findings indicate greater gastrointestinal absorption of copper and higher activity of dopamine-beta-hydroxylase, a copper-dependent enzyme, respectively. In family B, three males with a missense mutation (S637L) in an exon 8 splicing enhancer showed equally reduced amounts of ATP7A transcript and protein by quantitative RT-PCR and western blot analysis, respectively, despite a more severe phenotype in the youngest. This patient's medical history was notable for cardiac arrest as a neonate, to which we attribute his more severe neurodevelopmental outcome.
  
  
  CONCLUSIONS
  These families illustrate that genetic and non-genetic mechanisms may underlie intrafamilial variability in Menkes disease and its variants.
authors.affiliation: Unit on Pediatric Genetics, Laboratory of Clinical Genomics, National Institute of Child Health and Human Development, Bethesda, MD20892-1832, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Donsante
authors.forename: Jingrong
authors.initials: J
authors.lastname: Tang
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Godwin
authors.forename: Courtney S
authors.initials: CS
authors.lastname: Holmes
authors.forename: David S
authors.initials: DS
authors.lastname: Goldstein
authors.forename: Alexander
authors.initials: A
authors.lastname: Bassuk
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Kaler
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D027682:Cation Transport Proteins / Q000235:genetics*; D002460:Cell Line; D002531:Cerebellum / Q000002:abnormalities*; D002675:Child, Preschool; D003300:Copper / Q000378:metabolism; D000073840:Copper-Transporting ATPases; D004252:DNA Mutational Analysis; D005190:Family; D005786:Gene Expression Regulation; D005816:Genetic Complementation Test; D014644:Genetic Variation; D006801:Humans; D007223:Infant; D008297:Male; D007706:Menkes Kinky Hair Syndrome / Q000235:genetics*; D009778:Occipital Lobe / Q000002:abnormalities*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D035781:Siblings; D014158:Transcription, Genetic
chemical_list: D027682:Cation Transport Proteins; D003300:Copper; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases