title: Occipital horn syndrome and classical Menkes Syndrome caused by deep intronic mutations, leading to the activation of ATP7A pseudo-exon.
abstract: Menkes disease is an X-linked disorder of copper metabolism caused by mutations in the ATP7A gene. Whereas most of the patients exhibit a severe classical form, about 9% of the patients exhibit a milder form of Menkes disease. The mildest form is called occipital horn syndrome (OHS). Mutations in the ATP7A gene can be identified in 95-98% of the Menkes disease patients by standard screening techniques. Investigation of RNA isolated from the fibroblasts of eleven patients with no identified mutations was performed, and revealed inclusion of new pseudo-exons into the ATP7A mRNA from three unrelated patients: two patients with OHS and one patient with classical Menkes disease. The pseudo-exons were inserted between exons 10 and 11, between exons 16 and 17 and between exons 14 and 15 in the three patients, as a result of deep intronic mutations. This is the first time the activation of pseudo-exons is demonstrated in the ATP7A gene, and it demonstrates the usefulness of RNA analysis, in terms of revealing disease-causing mutations in noncoding regions. The fact that three different mutations cause disease by the activation of pseudo-exon inclusion also indicates that in Menkes disease this is an important mechanism, which has hitherto been overlooked.
authors.affiliation: Applied Human Molecular Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Gl. Landevej 7, Glostrup, Denmark.
authors.forename: Saiqa
authors.initials: S
authors.lastname: Yasmeen
authors.affiliation: Applied Human Molecular Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Gl. Landevej 7, Glostrup, Denmark.
authors.forename: Katrine
authors.initials: K
authors.lastname: Lund
authors.affiliation: Center for Medical Genetics, Ghent University, Ghent, Belgium.
authors.forename: Anne
authors.initials: A
authors.lastname: De Paepe
authors.affiliation: Center for Medical Genetics, Ghent University, Ghent, Belgium.
authors.forename: Sylvia
authors.initials: S
authors.lastname: De Bie
authors.affiliation: Department of medical genetics, Oslo University Hospital, National Hospital, Oslo, Norway.
authors.forename: Arvid
authors.initials: A
authors.lastname: Heiberg
authors.affiliation: Centro de Genética Preditiva e Preventiva, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.
authors.forename: João
authors.initials: J
authors.lastname: Silva
authors.affiliation: Trás-os-Montes e Alto Douro Hospital Center, Vila Real, Portugal.
authors.forename: Márcia
authors.initials: M
authors.lastname: Martins
authors.affiliation: Applied Human Molecular Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Gl. Landevej 7, Glostrup, Denmark.
authors.forename: Tina
authors.initials: T
authors.lastname: Skjørringe
authors.affiliation: Applied Human Molecular Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Gl. Landevej 7, Glostrup, Denmark.
authors.forename: Lisbeth B
authors.initials: LB
authors.lastname: Møller
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000293:Adolescent; D000483:Alleles; D001483:Base Sequence; D027682:Cation Transport Proteins / Q000235:genetics*; D002648:Child; D003300:Copper / Q000493:pharmacokinetics; D000073840:Copper-Transporting ATPases; D003483:Cutis Laxa / Q000175:diagnosis / Q000235:genetics*; D004535:Ehlers-Danlos Syndrome / Q000175:diagnosis / Q000235:genetics*; D005091:Exons; D006801:Humans; D007438:Introns; D008297:Male; D007706:Menkes Kinky Hair Syndrome / Q000175:diagnosis / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D017422:Sequence Analysis, DNA
chemical_list: D027682:Cation Transport Proteins; D012333:RNA, Messenger; D003300:Copper; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases