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.

Clinical utility gene card for: Menkes disease

“…However, these analyses demand specialised expertise and are performed only in a few centres around the world. 9 The ultimate diagnostic proof of MD is the demonstration of the molecular defect in ATP7A, which is located on chromosome Xq13.3. The 8.5-kb transcribed sequence of ATP7A is organised in 23 exons, in which the ATG start codon is in exon 2 and the last exon includes the TGA stop codon and a large 3¢ untranslated region (UTR).…”

“…To date, B210 different mutations (from chromosome aberrations to large deletions or duplications, and single-amino-acid substitutions) affecting ATP7A have been reported. [1][2][3][4][5][6][7][8][9] Chromosome abnormalities affecting ATP7A were detected in eight patients, one male 7 and seven female patients. One of the female patients was mosaic for the Turner karyotype and the rest had X;autosome translocations (reviewed in Sirleto et al 8 ).…”

“…Approximately one-third of the ATP7A mutations are gross deletions ranging in size from a single exon to deletion of the whole gene except for the first two exons, 6,9 and four patients have partial gene duplications. 9 The rest comprise B140 different intragenic mutations: missense (34%), nonsense (17%) and splice-site mutations (17%), and deletions/insertions/duplications (32%).…”

“…9 The rest comprise B140 different intragenic mutations: missense (34%), nonsense (17%) and splice-site mutations (17%), and deletions/insertions/duplications (32%). [1][2][3][4][5]9 There is no obvious correlation between the mutations and the clinical course of MD.…”

“…9 The rest comprise B140 different intragenic mutations: missense (34%), nonsense (17%) and splice-site mutations (17%), and deletions/insertions/duplications (32%). [1][2][3][4][5]9 There is no obvious correlation between the mutations and the clinical course of MD. However, in general, patients with a milder phenotype (such as OHS) have a higher proportion of mutations, which lead to a partially functional protein or result in reduced amounts of an otherwise normal protein.…”