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Occipital horn syndrome and classical Menkes Syndrome caused by deep intronic mutations, leading to the activation of ATP7A pseudo-exon.
Yasmeen, Saiqa; Lund, Katrine; De Paepe, Anne; De Bie, Sylvia; Heiberg, Arvid; Silva, João; Martins, Márcia; Skjørringe, Tina; Møller, Lisbeth B.
Affiliation
  • Yasmeen S; Applied Human Molecular Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Gl. Landevej 7, Glostrup, Denmark.
  • Lund K; Applied Human Molecular Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Gl. Landevej 7, Glostrup, Denmark.
  • De Paepe A; Center for Medical Genetics, Ghent University, Ghent, Belgium.
  • De Bie S; Center for Medical Genetics, Ghent University, Ghent, Belgium.
  • Heiberg A; Department of medical genetics, Oslo University Hospital, National Hospital, Oslo, Norway.
  • Silva J; Centro de Genética Preditiva e Preventiva, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.
  • Martins M; Trás-os-Montes e Alto Douro Hospital Center, Vila Real, Portugal.
  • Skjørringe T; Applied Human Molecular Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Gl. Landevej 7, Glostrup, Denmark.
  • Møller LB; Applied Human Molecular Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Gl. Landevej 7, Glostrup, Denmark.
Eur J Hum Genet ; 22(4): 517-21, 2014 Apr.
Article in En | MEDLINE | ID: mdl-24002164
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.
Subject(s)

Full text: 1 Database: MEDLINE Main subject: Adenosine Triphosphatases / Cutis Laxa / Cation Transport Proteins / Ehlers-Danlos Syndrome / Menkes Kinky Hair Syndrome Type of study: Diagnostic_studies / Prognostic_studies Limits: Adolescent / Child / Humans / Male Language: En Journal: Eur J Hum Genet Journal subject: GENETICA MEDICA Year: 2014 Type: Article Affiliation country: Denmark

Full text: 1 Database: MEDLINE Main subject: Adenosine Triphosphatases / Cutis Laxa / Cation Transport Proteins / Ehlers-Danlos Syndrome / Menkes Kinky Hair Syndrome Type of study: Diagnostic_studies / Prognostic_studies Limits: Adolescent / Child / Humans / Male Language: En Journal: Eur J Hum Genet Journal subject: GENETICA MEDICA Year: 2014 Type: Article Affiliation country: Denmark