title: A novel two-nucleotide deletion in the ATP7A gene associated with delayed infantile onset of Menkes disease.
abstract: BACKGROUND
  Determining the relationship between clinical phenotype and genotype in genetic diseases is important in clinical practice. In general, frameshift mutations are expected to produce premature termination codons, leading to production of mutant transcripts destined for degradation by nonsense-mediated decay. In X-linked recessive diseases, male patients with frameshift mutations typically have a severe or even lethal phenotype.
  
  
  METHODS
  We report a case of a 17-month-old boy with Menkes disease (NIM #309400), an X-linked recessive copper metabolism disorder caused by mutations in the ATP7A copper transporter gene. He exhibited an unexpectedly late onset and experienced milder symptoms.
  His genomic DNA showed a de novo two-nucleotide deletion in exon 4 of ATP7A, predicting a translational frameshift and premature stop codon, and a classic severe phenotype. Characterization of his ATP7A mRNA showed no abnormal splicing.
  
  
  CONCLUSIONS
  We speculate that translation reinitiation could occur downstream to the premature termination codon and produce a partially functional ATP7A protein. Study of the child's fibroblasts found no evidence of translation reinitiation; however, the possibility remains that this phenomenon occurred in neural tissues and influenced the clinical phenotype.
authors.affiliation: Department of Pediatric Neurology, Kanagawa Children's Medical Center, Yokohama, Kanagawa, Japan. Electronic address: takahito.wada0001@me.com.
authors.forename: Takahito
authors.initials: T
authors.lastname: Wada
authors.affiliation: The Unit on Human Copper Metabolism, Molecular Medicine Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.
authors.forename: Marie Reine
authors.initials: MR
authors.lastname: Haddad
authors.affiliation: The Unit on Human Copper Metabolism, Molecular Medicine Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.
authors.forename: Ling
authors.initials: L
authors.lastname: Yi
authors.affiliation: Department of Pediatric Neurology, Kanagawa Children's Medical Center, Yokohama, Kanagawa, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Murakami
authors.affiliation: Department of Pediatric Neurology, Kanagawa Children's Medical Center, Yokohama, Kanagawa, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Sasaki
authors.affiliation: Department of Pediatric Neurology, Kanagawa Children's Medical Center, Yokohama, Kanagawa, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Shimbo
authors.affiliation: Department of Health and Dietetics, Faculty of Health & Medical Sciences, Teikyo Heisei University, Tokyo, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Kodama
authors.affiliation: Department of Pediatric Neurology, Kanagawa Children's Medical Center, Yokohama, Kanagawa, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Osaka
authors.affiliation: The Unit on Human Copper Metabolism, Molecular Medicine Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Kaler
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D017668:Age of Onset; D001483:Base Sequence; D027682:Cation Transport Proteins / Q000235:genetics*; D000073840:Copper-Transporting ATPases; D004252:DNA Mutational Analysis; D016368:Frameshift Mutation; D006801:Humans; D007223:Infant; D008297:Male; D007706:Menkes Kinky Hair Syndrome / Q000235:genetics*; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D017384:Sequence Deletion
chemical_list: D027682:Cation Transport Proteins; D012333:RNA, Messenger; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases
keywords: ATP7A; Menkes disease; premature termination codon; translation reinitiation