Characterization of the exon structure of the Menkes disease gene using vectorette PCR

Tümer, Zeynep; Vural, Burçak; Tønnesen, T.; Chelly, Jamel; Monaco, Anthony P.; Horn, Nina

doi:10.1016/0888-7543(95)80160-n

Cited by 84 publications

(43 citation statements)

References 28 publications

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“…The majority of point mutations that have been identified in Menkes patients occur within exons 7-10, which encode MBS 6 and the first four transmembrane helices. All of the point mutations identified within the N terminus were either nonsense mutations or insertion/deletion mutations that are predicted to result in a truncation of the MNK gene product (29). These observations suggest that point mutations that disrupt the function of a single MBS are not likely to cause a disease phenotype and are supported by our findings that six functional MBSs are not necessary for MNK trafficking.…”

Section: Resultssupporting

confidence: 76%

The Role of GMXCXXC Metal Binding Sites in the Copper-induced Redistribution of the Menkes Protein

Strausak

Fontaine

Hill

et al. 1999

Journal of Biological Chemistry

151

130

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The Menkes protein (MNK or ATP7A) is a transmembrane, copper-transporting CPX-type ATPase, a subgroup of the extensive family of P-type ATPases. A striking feature of the protein is the presence of six metal binding sites (MBSs) in the N-terminal region with the highly conserved consensus sequence GMXCXXC. MNK is normally located in the trans-Golgi network (TGN) but has been shown to relocalize to the plasma membrane when cells are cultured in media containing high concentrations of copper. The experiments described in this report test the hypothesis that the six MBSs are required for this copper-induced trafficking of MNK. Site-directed mutagenesis was used to convert both cysteine residues in the conserved MBS motifs to serines. Mutation of MBS 1, MBS 6, and MBSs 1-3 resulted in a molecule that appeared to relocalize normally with copper, but when MBSs 4 -6 or MBSs 1-6 were mutated, MNK remained in the TGN, even when cells were exposed to 300 M copper. Furthermore, the ability of the MNK variants to relocalize corresponded well with their ability to confer copper resistance. To further define the critical motifs, MBS 5 and MBS 6 were mutated, and these changes abolished the response to copper. The region from amino acid 8 to amino acid 485 was deleted, resulting in mutant MNK that lacked 478 amino acids from the N-terminal region, including the first four MBSs. This truncated molecule responded normally to copper. Moreover, when either one of the remaining MBS 5 and MBS 6 was mutated to GMXSXXS, the resulting proteins were localized to the TGN in low copper and relocalized in response to elevated copper. These experiments demonstrated that the deleted N-terminal region from amino acid 8 to amino acid 485 was not essential for copper-induced trafficking and that one MBS close to the membrane channel of MNK was necessary and sufficient for the copper-induced redistribution.

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Section: Resultssupporting

confidence: 76%

The Role of GMXCXXC Metal Binding Sites in the Copper-induced Redistribution of the Menkes Protein

Strausak

Fontaine

Hill

et al. 1999

Journal of Biological Chemistry

151

130

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“…The structure of the human Menkes gene has been characterized, and molecular genetic analysis of affected patients reveals that at least 30% of individuals with Menkes disease have deletions or mutations which should eliminate expression of this gene (3,(36)(37). The availability of specific antibodies may therefore be useful for diagnosis in circumstances where clinical material is limited or the lack of family data precludes focused molecular analysis.…”

Section: Discussionmentioning

confidence: 99%

Biochemical characterization and intracellular localization of the Menkes disease protein

Yamaguchi

Heiny

Suzuki

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

193

143

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“…The 8.5-kb transcribed sequence of ATP7A is organized in 23 exons, which span a 140-kb genomic region 27 (UCSC Genome Browser; http://genome.cse.ucsc.edu/). 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).…”

Section: Genetic Basis Of MDmentioning

confidence: 99%

Menkes disease

Tümer

Møller²

2009

Eur J Hum Genet

328

276

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Characterization of the exon structure of the Menkes disease gene using vectorette PCR

Cited by 84 publications

References 28 publications

The Role of GMXCXXC Metal Binding Sites in the Copper-induced Redistribution of the Menkes Protein

The Role of GMXCXXC Metal Binding Sites in the Copper-induced Redistribution of the Menkes Protein

Biochemical characterization and intracellular localization of the Menkes disease protein

Menkes disease

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