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ATP7A mutations in 66 Japanese patients with Menkes disease and carrier detection: A gene analysis
Chie Fujisawa1, Hiroko Kodama1,2, Tomoko Hiroki1
1Department of Pediatrics, Teikyo University School of Medicine, Tokyo, Japan.
Background:
Menkes disease (MNK; MIN 309400) is an X-linked recessive lethal disorder of copper metabolism caused by mutations in ATP7A (MIM 300011), which encodes a transmembrane copper-transporting P-type ATPase. This study assessed mutations in ATP7A in Japanese patients with MNK and their families using gene analysis.
Methods:
A total of 66 patients with MNK born between 1975 and 2013 in Japan were investigated in this study. Definite diagnosis of MNK was carried out on polymerase chain reaction (PCR) amplification and direct sequencing of each exon. Genetic analysis was also performed on 39 women for carrier diagnosis, and on nine fetuses and 10 neonates for the diagnosis of MNK.
Results:
We detected 55 different mutations, of which 20 were de novo mutations. The mutations were located around the six copper binding sites, first to third and six transmembrane domains, and the ATP binding site. Of 30 mothers, 23 (76.7%) were carriers. Approximately half of the male siblings of patients with MNK were also diagnosed with MNK.
Conclusion:
Mutations in ATP7A varied widely across patients, although approximately half of the mutations were located in exons 4, 9, 10, and 15. Approximately 23% of patients did not inherit the mutations from their mothers, but had de novo mutations. An early definite diagnosis is necessary for the early treatment of MNK, and gene analysis serves as an effective method for detecting mutations in ATP7A.
Insights
Genetic analysis of ATP7A mutations in Japanese Menkes disease (MNK) patients identified 55 unique mutations, aiding early diagnosis. Gene analysis is crucial for identifying these copper metabolism disorder mutations.
Area of Science:
- Genetics
- Molecular Biology
- Biochemistry
Background:
- Menkes disease (MNK) is a lethal X-linked recessive disorder of copper metabolism.
- It is caused by mutations in the ATP7A gene, which encodes a copper-transporting ATPase.
Purpose of the Study:
- To assess ATP7A mutations in Japanese patients with Menkes disease.
- To evaluate the utility of gene analysis for diagnosing MNK and identifying carriers.
Main Methods:
- Investigated 66 Japanese MNK patients born between 1975 and 2013.
- Utilized polymerase chain reaction (PCR) amplification and direct sequencing of ATP7A exons.
- Conducted genetic analysis for carrier diagnosis in 39 women and prenatal/neonatal diagnosis in 19 infants.
Main Results:
- Identified 55 distinct ATP7A mutations, including 20 de novo mutations.
- Mutations were concentrated around copper binding sites, transmembrane domains, and the ATP binding site.
- Confirmed carrier status in 76.7% of mothers and diagnosed MNK in approximately half of male siblings.
Conclusions:
- ATP7A mutations exhibit significant variability among MNK patients.
- Approximately 23% of cases involved de novo mutations, not inherited from mothers.
- Gene analysis is an effective tool for early and definite diagnosis of MNK, facilitating timely treatment.
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