Screening of 383 unrelated patients affected with Menkes disease and finding of 57 gross deletions inATP7A

Abstract

Menkes disease (MD) is an X-linked multisystemic lethal disorder of copper metabolism dominated by neurodegenerative symptoms and connective tissue disturbances. MD results from mutations in the ATP7A gene, which encodes a membrane-bound copper transporting P-type ATPase located in the trans-Golgi network. In this study we describe screening of 383 unrelated patients affected with Menkes disease for gross deletions in ATP7A gene and finding of 57 patients. The present data suggests that gross deletion of ATP7A is the disease-causing mutation in 14.9% of the Menkes disease patients. Except for a few cases, gross gene deletions result in the classical form of Menkes disease with death in early childhood.

Menkes disease

“…41 Presence of partially functional, truncated protein variants missing only part of the C-terminus might also result in OHS or a mild Menkes phenotype. 31,42 Interestingly, in a patient with a mild phenotype we have detected deletion of exons 3-4, which resulted in a premature stop codon just at the beginning of exon 5, but translation was reinitiated from a downstream start codon. 43 This truncated protein was partially functional with only two copper-binding domains (MBD 5-6), resulting in milder symptoms.…”

“…To date about 170 different mutations (from single-amino-acid substitutions to large deletions and chromosome aberrations) affecting ATP7A have been reported [28][29][30][31][32] (Human Gene Mutation Database (HGMD); www.hgmd.org).…”

“…Approximately 25% of the ATP7A mutations (n¼50) are gross deletions ranging in size from a single exon to deletion of the whole gene except for the first two exons. 31 To date about 120 different intragenic mutations of ATP7A have been reported: missense (33%), nonsense (16%) and splice-site mutations (16%), and deletions/insertions/duplications (33%) (HGMD). 28,29,32 About half of the point mutations (deletions/insertions/duplications and nonsense mutations) are truncating mutations, which are shown or predicted to result in a non-functional truncated protein.…”

Clinical utility gene card for: Menkes disease

“…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%).…”