Identification and analysis of 21 novel disease-causing amino acid substitutions in the conserved part of ATP7A

Abstract

ATP7A encodes a copper-translocating ATPase that belongs to the large family of P-type ATPases. Eight conserved regions define the core of the P-type ATPase superfamily. We report here the identification of 21 novel missense mutations in the conserved part of ATP7A that encodes the residues p.V842-p.S1404. Using the coordinates of X-ray crystal structures of the sarcoplasmic reticulum Ca(2+)-ATPase, as determined in the presence and absence of Ca(2+), we created structural homology models of ATP7A. By mapping the substituted residues onto the models, we found that these residues are more clustered three-dimensionally than expected from the primary sequence. The location of the substituted residues in conserved regions supports the functional similarities between the two types of P-type ATPases. An immunofluorescence analysis of Menkes fibroblasts suggested that the localization of a large number of the mutated ATP7A protein variants was correct. In the absence of copper, they were located in perinuclear regions of the cells, just like the wild type. However, two of the mutated ATP7A variants showed only partly correct localization, and in five cultures no ATP7A protein could be detected. These findings suggest that although a disease-causing mutation may indicate a functional significance of the affected residue, this is not always the case.

Insights into the mechanisms of copper dyshomeostasis in amyotrophic lateral sclerosis

“…Neurological disorders associated with defects in copper transporting ATPases On the one hand, mutations in ATP7A are associated with Menkes disease (MNKD) (Refs 18,19) and distal spinal muscular atrophy, X-linked, 3 (DSMAX3) (Ref. 20), both of which are characterised by generalised copper deficiency.…”

Menkes disease

“…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).…”

“…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. These truncating mutations are distributed almost equally throughout the gene, and they are predicted to have detrimental effects on the protein function.…”

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 ).…”

“…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.…”