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

Publication: Research - peer-reviewJournal article – Annual report year: 2005

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Identification and analysis of 21 novel disease-causing amino acid substitutions in the conserved part of ATP7A. / Moller, L.B.; Bukrinsky, J.T.; Mølgaard, Anne; Paulsen, M.; Lund, C.; Tumer, Z.; Larsen, S.; Horn, N.

In: Human Mutation, Vol. 26, No. 2, 2005, p. 84-93.

Publication: Research - peer-reviewJournal article – Annual report year: 2005

Harvard

Moller, LB, Bukrinsky, JT, Mølgaard, A, Paulsen, M, Lund, C, Tumer, Z, Larsen, S & Horn, N 2005, 'Identification and analysis of 21 novel disease-causing amino acid substitutions in the conserved part of ATP7A' Human Mutation, vol 26, no. 2, pp. 84-93.

APA

Moller, L. B., Bukrinsky, J. T., Mølgaard, A., Paulsen, M., Lund, C., Tumer, Z., ... Horn, N. (2005). Identification and analysis of 21 novel disease-causing amino acid substitutions in the conserved part of ATP7A. Human Mutation, 26(2), 84-93.

CBE

Moller LB, Bukrinsky JT, Mølgaard A, Paulsen M, Lund C, Tumer Z, Larsen S, Horn N. 2005. Identification and analysis of 21 novel disease-causing amino acid substitutions in the conserved part of ATP7A. Human Mutation. 26(2):84-93.

MLA

Vancouver

Author

Moller, L.B.; Bukrinsky, J.T.; Mølgaard, Anne; Paulsen, M.; Lund, C.; Tumer, Z.; Larsen, S.; Horn, N. / Identification and analysis of 21 novel disease-causing amino acid substitutions in the conserved part of ATP7A.

In: Human Mutation, Vol. 26, No. 2, 2005, p. 84-93.

Publication: Research - peer-reviewJournal article – Annual report year: 2005

Bibtex

@article{984135d6d80d4cc5acd830b86b295f41,
title = "Identification and analysis of 21 novel disease-causing amino acid substitutions in the conserved part of ATP7A",
keywords = "ATP7A, structure, localization, P-type ATPases, copper transport, stability, missense mutations",
author = "L.B. Moller and J.T. Bukrinsky and Anne Mølgaard and M. Paulsen and C. Lund and Z. Tumer and S. Larsen and N. Horn",
year = "2005",
volume = "26",
pages = "84--93",
journal = "Human Mutation",
issn = "1059-7794",
publisher = "John/Wiley & Sons, Inc. John/Wiley & Sons Ltd.",
number = "2",

}

RIS

TY - JOUR

T1 - Identification and analysis of 21 novel disease-causing amino acid substitutions in the conserved part of ATP7A

AU - Moller,L.B.

AU - Bukrinsky,J.T.

AU - Mølgaard,Anne

AU - Paulsen,M.

AU - Lund,C.

AU - Tumer,Z.

AU - Larsen,S.

AU - Horn,N.

PY - 2005

Y1 - 2005

N2 - 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 Ca2+-ATPase, as determined in the presence and absence of Ca2+, 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.

AB - 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 Ca2+-ATPase, as determined in the presence and absence of Ca2+, 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.

KW - ATP7A

KW - structure

KW - localization

KW - P-type ATPases

KW - copper transport

KW - stability

KW - missense mutations

M3 - Journal article

VL - 26

SP - 84

EP - 93

JO - Human Mutation

T2 - Human Mutation

JF - Human Mutation

SN - 1059-7794

IS - 2

ER -