Abstract
BackgroundMenkes disease (MD) is an X-linked, fatal neurodegenerative disorder of copper metabolism, caused by mutations in the ATP7A gene. Thirty-three Menkes patients in whom no mutation had been detected with standard diagnostic tools were screened for exon duplications in the ATP7A gene.MethodsThe ATP7A gene was screened for exon duplications using multiplex ligation-dependent probe amplification (MLPA). The expression level of ATP7A was investigated by real-time PCR and detailed analysis of the ATP7A mRNA was performed by RT-PCR followed by sequencing. In order to investigate whether the identified duplicated fragments originated from a single or from two different X-chromosomes, polymorphic markers located in the duplicated fragments were analyzed.ResultsPartial ATP7A gene duplication was identified in 20 unrelated patients including one patient with Occipital Horn Syndrome (OHS). Duplications in the ATP7A gene are estimated from our material to be the disease causing mutation in 4% of the Menkes disease patients. The duplicated regions consist of between 2 and 15 exons. In at least one of the cases, the duplication was due to an intra-chromosomal event. Characterization of the ATP7A mRNA transcripts in 11 patients revealed that the duplications were organized in tandem, in a head to tail direction. The reading frame was disrupted in all 11 cases. Small amounts of wild-type transcript were found in all patients as a result of exon-skipping events occurring in the duplicated regions. In the OHS patient with a duplication of exon 3 and 4, the duplicated out-of-frame transcript coexists with an almost equally represented wild-type transcript, presumably leading to the milder phenotype.ConclusionsIn general, patients with duplication of only 2 exons exhibit a milder phenotype as compared to patients with duplication of more than 2 exons. This study provides insight into exon duplications in the ATP7A gene.
Highlights
Menkes disease (MD) is an X-linked, fatal neurodegenerative disorder of copper metabolism, caused by mutations in the ATP7A gene
The neurological symptoms of Occipital Horn Syndrome (OHS) patients are milder than those found in patients with atypical MD and lead to a clinical picture mainly characterized by connective tissue manifestations
The majority of MD patients display the phenotype of classical MD, but milder phenotypes are seen in about 9% of the patients, and approximately one third of these have OHS [6]
Summary
Menkes disease (MD) is an X-linked, fatal neurodegenerative disorder of copper metabolism, caused by mutations in the ATP7A gene. Menkes disease (MD; MIM# 309400) is a multisystemic lethal disorder of impaired copper metabolism due to mutations in the X-linked ATP7A gene [1,2]. The ATP7A protein is a member of the P-type ATPase family that ensures the ATP-driven translocation of metal cations across cellular membranes. At normal physiological copper concentrations, ATP7A is categories: classical MD which leads to death in early childhood, the less severe atypical MD with longer survival, and the mildest allelic form Occipital Horn Syndrome (OHS). The neurological symptoms of OHS patients are milder than those found in patients with atypical MD and lead to a clinical picture mainly characterized by connective tissue manifestations. The majority of MD patients display the phenotype of classical MD, but milder phenotypes are seen in about 9% of the patients, and approximately one third of these have OHS [6]
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