Identification of novel ATP7A mutations and prenatal diagnosis in Chinese patients with Menkes disease
Binbin CaoXiaoping YangYinyin ChenQionghui HuangYe WuQiang GuJiangxi XiaoHuixia YangHong PanJunya ChenYu SunLi RenChengfeng ZhaoYanhua DengYanling YangXingzhi ChangZhixian YangYuehua ZhangZhengping NiuJuli WangXiru WuJingmin WangYuwu Jiang
10
Citation
32
Reference
10
Related Paper
Citation Trend
Keywords:
ATP7A
Menkes disease
Nonsense mutation
Proband
Compound heterozygosity
The trace metal copper is essential for a variety of biological processes, but extremely toxic when present in excessive amounts. Therefore, concentrations of this metal in the body are kept under tight control. Central regulators of cellular copper metabolism are the copper-transporting P-type ATPases ATP7A and ATP7B. Mutations in ATP7A or ATP7B disrupt the homeostatic copper balance, resulting in copper deficiency (Menkes disease) or copper overload (Wilson disease), respectively. ATP7A and ATP7B exert their functions in copper transport through a variety of interdependent mechanisms and regulatory events, including their catalytic ATPase activity, copper-induced trafficking, post-translational modifications and protein–protein interactions. This paper reviews the extensive efforts that have been undertaken over the past few years to dissect and characterise these mechanisms, and how these are affected in Menkes and Wilson disease. As both disorders are characterised by an extensive clinical heterogeneity, we will discus how the underlying genetic defects correlate with the molecular functions of ATP7A and ATP7B and with the clinical expression of these disorders.
Menkes disease
ATP7A
Copper deficiency
P-type ATPase
Cite
Citations (372)
The gene ATP7A encodes for the copper-transporting ATPase ATP7A, important for regulating copper [Cu (I)] level in the cells. In the small intestine, the ATP7A protein helps controlling the absorption of Cu (I) from food. The ATP7A gene contains 23 exons. Pathogenic variants in the gene, ATP7A, results in two different copper-deficiency disorder, occipital horn syndrome (OHS; OMIM #304150) and the more severe form, Menkes disease (MD; OMIM #309400).
ATP7A
Menkes disease
Cite
Citations (0)
Menkes' disease is an inherited disorder of copper homeostasis that arises from a deficiency in copper-transporting P-type ATPase, the mouse gene for which is designated Atp7a. The macular and the viable-brindled mouse are among Menkes' disease models and have been shown to have respective single missense mutations in their genes. In this study we tested whether these mutations are a cause of the disease. Yeast strain Δccc2, lacking CCC2, the yeast homologue of Atp7a, was used to examine whether this mutant yeast can be rescued by expression of acular or viable-brindled Atp7a protein when cultured in copper- and iron-deficient medium. Expression of both mutant Atp7a proteins was found to enable the growth of Δccc2 yeast, but the growth rates were less than one-fifth of the rate observed for Δccc2 yeast expressing wild-type Atp7a protein. Thus it is clear that the missense mutations of both animal models for Menkes' disease are responsible for the impaired function of copper transport.
ATP7A
Menkes disease
Copper deficiency
Wild type
Cite
Citations (0)
The ATP7A gene encodes the ATP7A protein, which is a trans-Golgi network copper transporter expressed in the brain and other organs. Mutations in this gene cause disorders of copper metabolism, such as Menkes disease. Here we describe the novel and unusual mutation (p.T1048I) in the ATP7A gene of a child with Menkes disease. The mutation affects a conserved DKTGT1048 phosphorylation motif that is involved in the catalytic activity of ATP7A. We also describe the clinical course and the response to copper treatment in this patient.An 11-month-old male Caucasian infant was studied because of hypotonia, ataxia and global developmental delay. The patient presented low levels of serum copper and ceruloplasmin, and was shown to be hemizygous for the p.T1048I mutation in ATP7A. The diagnosis was confirmed when the patient was 18 months old, and treatment with copper-histidinate (Cu-His) was started immediately. The patient showed some neurological improvement and he is currently 8 years old. Because the p.T1048I mutation affects its catalytic site, we expected a complete loss of functional ATP7A and a classical Menkes disease presentation. However, the clinical course of the patient was mild, and he responded to Cu-His treatment, which suggests that this mutation leads to partial conservation of the activity of ATP7A.This case emphasizes the important correlation between genotype and phenotype in patients with Menkes disease. The prognosis in Menkes disease is associated with early detection, early initiation of treatment and with the preservation of some ATP7A activity, which is necessary for Cu-His treatment response. The description of this new mutation and the response of the patient to Cu-His treatment will contribute to the growing body of knowledge about treatment response in Menkes disease.
ATP7A
Menkes disease
Cite
Citations (5)
Abstract Protein translation ends when a stop codon in a gene's messenger RNA transcript enters the ribosomal A site. Mutations that create premature stop codons (nonsense mutations) typically cause premature translation termination. An alternative outcome, read‐through translation (or nonsense suppression), is well known in prokaryotic, viral, and yeast genes but has not been clearly documented in humans except in the context of pharmacological manipulations. Here, we identify and characterize native read‐through of a nonsense mutation (R201X) in the human copper transport gene, ATP7A. Western blotting, in vitro expression analyses, immunohistochemistry, and yeast complementation assays using cultured fibroblasts from a classic Menkes disease patient all indicated small amounts of native ATP7A R201X read‐through and were associated with a dramatic clinical response to early copper treatment. Ann Neurol 2009;65:108–113
Menkes disease
Nonsense mutation
ATP7A
Nonsense
Stop codon
Cite
Citations (34)
Menkes disease (MD) is an X-linked multisystemic lethal disorder of copper metabolism dominated by neurodegenerative symptoms and connective tissue disturbances. MD results from mutations in the ATP7A gene, which encodes a membrane-bound copper transporting P-type ATPase located in the trans-Golgi network. In this study we describe screening of 383 unrelated patients affected with Menkes disease for gross deletions in ATP7A gene and finding of 57 patients. The present data suggests that gross deletion of ATP7A is the disease-causing mutation in 14.9% of the Menkes disease patients. Except for a few cases, gross gene deletions result in the classical form of Menkes disease with death in early childhood. Hum Mutat 22:457–464, 2003. © 2003 Wiley-Liss, Inc.
Menkes disease
ATP7A
Cite
Citations (67)
Background: Menkes disease is a congenital neurodegenerative disorder caused by ATP7A gene mutations. Clinical features include epilepsy, growth delay, reduced muscle strength, skin laxity, abnormal hair, and urologic abnormalities. Case presentation: We describe an infant with developmental delay, neurologic degeneration, and kinky hair. Molecular test revealed a novel heterozygous mutation in exon 21 of the ATP7A gene. The genotype and phenotype of the patient were compared with those of the patients reported in the literature. Conclusion: We propose that this mutation caused a dysfunctional protein resulting in classical Menkes disease. This case adds to the spectrum of pathogenic variants of the ATP7A gene known to cause disease. Keywords: Menkes disease, ATP7A gene, copper-transporting ATPasa, genodermatosis
Menkes disease
ATP7A
Genodermatosis
Genotype-phenotype distinction
Cite
Citations (14)
Menkes disease is an X-linked copper deficiency disorder that results from mutations in the ATP7A (MNK) gene. A wide range of disease-causing mutations within ATP7A have been described, which lead to a diversity of phenotypes exhibited by Menkes patients. The mottled locus (Mo, Atp7a, Mnk) represents the murine homologue of the ATP7A gene, and the mottled mutants exhibit a diversity of phenotypes similar to that observed among Menkes patients. Therefore, these mutants are valuable models for studying Menkes disease. Two of the mottled mutants are brindled and blotchy and their pheno-types resemble classical Menkes disease and occipital horn syndrome (OHS) in humans, respectively. That is, the brindled mutant and patients with classical Menkes disease are severely copper deficient and have profound neurological problems, while OHS patients and the blotchy mouse have a much milder phenotype with predominantly connective tissue defects. In this study, in an attempt to understand the basis for the brindled and blotchy phenotypes, the copper transport characteristics and intracellular distribution of the Mnk protein were assessed in cultured cells from these mutants. The results demonstrated that the abnormal copper metabolism of brindled and blotchy cells may be related to a number of factors, which include the amount of Mnk protein, the intracellular location of the protein and the ability of Mnk to redistribute in elevated copper. The data also provide evidence for a relationship between the copper transport function and copper-dependent trafficking of Mnk.
Menkes disease
ATP7A
Copper deficiency
Wild type
Cite
Citations (60)
Menkes disease is a multi-systemic copper metabolism disorder caused by mutations in the X-linked ATP7A gene and characterised by progressive neurodegeneration and severe connective tissue defects. The ATP7A protein is a Copper (Cu)-transporting ATPase expressed in all tissues and plays a critical role in the maintenance of copper homeostasis in cells of the whole body. ATP7A participates in copper absorption in the small intestine and in copper transport to the CNS across the blood-brain-barrier and blood–cerebrospinal fluid- barrier. Cu is essential for synaptogenesis and axonal development. In cells, ATP7A participates in the incorporation of copper into Cu-dependent enzymes during the course of its maturation in the secretory pathway. There is a high degree of homology (>80% ) between the human ATP7A and murine Atp7a genes. Mice with mutations in the Atp7a gene, called mottled mutants, are well-established and excellent models of Menkes disease. Mottled mutants closely recapitulate the Menkes phenotype and are invaluable for studying Cu-metabolism. They provide useful models for exploring and testing new forms of therapy in Menkes disease. Recently, non-mammalian models of Menkes disease, Drosophila melanogaster and Danio rerio mutants were used in experiments which would be technically difficult to carry out in mammals.
Menkes disease
Animal model
Cite
Citations (26)
Menkes disease is a fatal genetic copper deficiency. The Menkes protein (ATP7A) was found to remove copper from tissues in mice that expressed the human ATP7A. Promising results were obtained with the use of a new copper complex for treatment of Menkes disease using a mouse model.
ATP7A
Menkes disease
Copper deficiency
Homeostasis
Cite
Citations (0)