title: Twenty-five novel mutations including duplications in the ATP7A gene.
abstract: Twenty-five novel mutations including duplications in the ATP7A gene. Menkes disease (MD) and occipital horn syndrome (OHS) are allelic X-linked recessive copper deficiency disorders resulting from ATP7A gene mutations. MD is a severe condition leading to progressive neurological degeneration and death in early childhood, whereas OHS has a milder phenotype with mainly connective tissue abnormalities. Until now, molecular analyses have revealed only deletions and point mutations in both diseases. This study reports new molecular data in a series of 40 patients referred for either MD or OHS. We describe 23 point mutations (9 missense mutations, 7 splice site variants, 4 nonsense mutations, and 3 small insertions or deletions) and 7 intragenic deletions. Of these, 18 point mutations and 3 deletions are novel. Furthermore, our finding of four whole exon duplications enlarges the mutation spectrum in the ATP7A gene. ATP7A alterations were found in 85% of cases. Of these alterations, two thirds were point mutations and the remaining one third consisted of large rearrangements. We found that 66.6% of point mutations resulted in impaired ATP7A transcript splicing, a phenomenon more frequent than expected. This finding enabled us to confirm the pathogenic role of ATP7A mutations, particularly in missense and splice site variants.
authors.affiliation: CHRU de Tours, Service de Génétique, Tours, F-37044, France INSERM U930, Tours, F-37044, France CHU Hôpital Purpan, Service de Génétique médicale, Toulouse, F-31059, France CHU Hôpital d'Enfants Armand-Trousseau, AP-HP, Service de Génétique et Embryologie médicales, Paris, F-75571, France CHU Hôpital d'Enfants Armand-Trousseau, AP-HP, Service de Neuropédiatrie, Paris, F-75012, France Genetica Medica, Università di Pavia, Fondazione IRCCS S. Matteo, Pavia, I-27100, Italie Centre de Référence des Maladies Héréditaires du Métabolisme, INSERM U954. Hôpital d'Enfants, Vandoeuvre les Nancy, F-54511, France CHRU de Tours, Service de Neuropédiatrie, Tours, F-37044 France; Université François Rabelais Tours, F-37044, France.
authors.forename: M-P
authors.initials: MP
authors.lastname: Moizard
authors.forename: N
authors.initials: N
authors.lastname: Ronce
authors.forename: S
authors.initials: S
authors.lastname: Blesson
authors.forename: E
authors.initials: E
authors.lastname: Bieth
authors.forename: L
authors.initials: L
authors.lastname: Burglen
authors.forename: C
authors.initials: C
authors.lastname: Mignot
authors.forename: I
authors.initials: I
authors.lastname: Mortemousque
authors.forename: N
authors.initials: N
authors.lastname: Marmin
authors.forename: B
authors.initials: B
authors.lastname: Dessay
authors.forename: C
authors.initials: C
authors.lastname: Danesino
authors.forename: F
authors.initials: F
authors.lastname: Feillet
authors.forename: P
authors.initials: P
authors.lastname: Castelnau
authors.forename: A
authors.initials: A
authors.lastname: Toutain
authors.forename: C
authors.initials: C
authors.lastname: Moraine
authors.forename: M
authors.initials: M
authors.lastname: Raynaud
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D027682:Cation Transport Proteins / Q000235:genetics*; D000073840:Copper-Transporting ATPases; D003483:Cutis Laxa / Q000235:genetics* / Q000473:pathology; D004535:Ehlers-Danlos Syndrome / Q000235:genetics* / Q000473:pathology; D005091:Exons / Q000235:genetics; D005260:Female; D020440:Gene Duplication / Q000235:genetics*; D020869:Gene Expression Profiling; D015321:Gene Rearrangement / Q000235:genetics; D006801:Humans; D008297:Male; D007706:Menkes Kinky Hair Syndrome / Q000235:genetics* / Q000473:pathology; D060885:Multiplex Polymerase Chain Reaction; D020125:Mutation, Missense / Q000235:genetics; D017354:Point Mutation / Q000235:genetics*; D022821:RNA Splice Sites / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics*
chemical_list: D027682:Cation Transport Proteins; D022821:RNA Splice Sites; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases