Identification of three novel mutations in the MNK gene in three unrelated Japanese patients with classical Menkes disease

Ogawa, Atsushi; Yamamoto, Shozo; Takayanagi, Masaki; Kogo, Toshiaki; Kanazawa, Masato; Kohno, Yoichi

doi:10.1007/s100380050144

Cited by 16 publications

(11 citation statements)

References 4 publications

(5 reference statements)

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“…These included nine missense mutations, six splice site alterations, four nonsense mutations and three small deletions or insertions that were predicted to cause a frameshift. Among the point mutations, five have been previously described (16, 23, 24). None of the missense substitutions identified were found in 96 male control samples.…”

Section: Resultsmentioning

confidence: 88%

Twenty-five novel mutations including duplications in the ATP7A gene

Ronce

Blesson

et al. 2011

Clinical Genetics

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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.

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Section: Resultsmentioning

confidence: 88%

Twenty-five novel mutations including duplications in the ATP7A gene

Ronce

Blesson

et al. 2011

Clinical Genetics

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“…Together with nine mutations reported earlier [Das et al, 1994;Tümer et al, 1997;Levinson et al, 1997;Kaler 1998;Ambrosini and Mercer, 1999;Ogawa et al, 1999;Gu et al, 2001;Hahn et al, 2001] and four mutations in the murine homologue, atp7a [Cecchi et al, 1997;Levinson et al, 1997;Mori and Nishimura, 1997;Murata et al, 1997;Ohta et al, 1997;Reed and Boyd, 1997], a total number of 34 missense mutations are known to date in the part of ATP7A/ atp7a sequence encoding residues p.V842-p.S1404. The total number of substituted residues in this region is 30 (Table 1).…”

Section: Identi¢cation Of Missense Mutations In the Atp7a Genementioning

confidence: 93%

“…About 110 mutations have been reported in ATP7A in affected patients [reviewed in Tümer et al, 1999] (see the Human Gene Mutation Database at http://archive.uwcm.ac.uk/uwcm/mg/ hgmd0.html), only 14 of which are missense mutations [Das et al, 1994;Kaler, 1998;Levinson et al, 1997;Tümer et al, 1997Tümer et al, , 1999Ambrosini and Mercer, 1999;Ogawa et al, 1999;Hahn et al, 2001;Gu et al, 2001].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2005

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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.

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“…Over 200 disease-causing variants have been identified in MNK patients. A literature search was performed to assemble the various ATP7A mutations available (Ambrosini and Mercer 1999; Beck et al 1994;Chelly et al 1993;Dagenais et al 2001;Das et al 1994Das et al , 1995Gu et al 2001;Hahn et al 2001;Kaler et al 1994Kaler et al , 1995Kapur et al 1987;Levinson et al 1996;Mak et al 2002;Møller et al 2000;Ogawa et al 1999aOgawa et al , 1999bOgawa et al , 2000Ozawa et al 2001;Qi and Byers 1998;Ronce et al 1997;Tümer et al 1992Tümer et al , 1994bTümer et al , 1996Vulpe et al 1993). We accessed 87 MNK patient point mutations identified in ATP7A for use in our comparisons (see Table 1).…”

Section: Mutation Comparisonmentioning

confidence: 99%

A comparison of the mutation spectra of Menkes disease and Wilson disease

Hsi

Cox

2004

Human Genetics

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The genes for two copper-transporting ATPases, ATP7A and ATP7B, are defective in the heritable disorders of copper imbalance, Menkes disease (MNK) and Wilson disease (WND), respectively. A comparison of the two proteins shows extensive conservation in the signature domains, with amino acid identities outside of the conserved domains being limited. The mutation spectra of MNK and WND were compared to confirm and refine further regions critical for normal function. Mutations were found to be relatively widespread; however, the majority was concentrated within defined functional domains and membrane-spanning segments, reinforcing the importance of these regions for protein function. Of the total published point mutations in ATP7A, 23.0% are splice-site, 20.7% nonsense, 17.2% missense, and 39.1% small insertions/deletions. There is a high prevalence (58.2%) of missense mutations in ATP7B. For the other mutations in ATP7B, 7.4% are splice-site, 7.4% nonsense, and 27.0% small insertions/deletions. A region of possible importance is the intervening sequence between the last copper-binding domain and the first transmembrane helix, as this region has a high percentage of MNK mutations. Similarly, the region containing the ATP-binding domain has 24.6% of all WND mutations. The study of mutation locations is useful for defining critical regions or residues and for efficient molecular diagnosis.

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Identification of three novel mutations in the MNK gene in three unrelated Japanese patients with classical Menkes disease

Cited by 16 publications

References 4 publications

Twenty-five novel mutations including duplications in the ATP7A gene

Twenty-five novel mutations including duplications in the ATP7A gene

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

A comparison of the mutation spectra of Menkes disease and Wilson disease

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