The T1048I mutation in ATP7A gene causes an unusual Menkes disease presentation

Abstract

Background: 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.

Case presentation: 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.

Conclusion: 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.

Figure 1

A) Transmembrane organization of the human ATP7A protein. This schematic representation is based on structural studies of ATP7A [7]. ATP7A contains five regions: i) an N-terminal tail with six metal-binding sites (MBS 1–6), ii) eight trans-membrane segments (TMS), iii) an ATP-binding domain that contains a nucleotide-binding motif (N-domain) and a phosphorylation motif (P-domain, DKTGT¹⁰⁴⁸), iv) an A-domain and v) a C-terminal tail. B) Presence of ATP7A gene mutation (c.3288 C > T), and copper, ceruloplasmin and β-2 microglobulin levels in the patient and in members of his family. The patient’s serum levels of copper and ceruloplasmin were measured while he was receiving Cu-His (100 μg/kg/day). The urine level of β-2 microglobulin was determined 6.5 years after the administration of Cu-His (normal range, 30–370 μg/24 h).

Figure 2

A) Restriction fragment length polymorphism (RFLP) assay. Exon 16 of the ATP7A gene was amplified using specific primers, and the PCR product was digested with HinfI. The c.3288 C > T mutation introduces a HinfI restriction site that divides the 107 bp fragment into two fragments of 79 and 28 bp. ud PCR, undigested PCR. B) DNA sequence of part of the ATP7A gene (exon 16) from the patient and from a normal control; the mutation is shown in red.