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| Content Provider | PubMed Central |
|---|---|
| Author | Tang, Jingrong Anthony, Donsante Desai, Vishal Nicholas, Patronas Kaler, Stephen G. |
| Abstract | Menkes disease is a fatal neurodegenerative disorder of infancy caused by defects in an X-linked copper transport gene, ATP7A. Evidence from a recent clinical trial indicates that favorable response to early treatment of this disorder with copper injections involves mutations that retain some copper transport capacity. In three unrelated infants, we identified the same mutation, G727R, in the second transmembrane segment of the ATP7A gene product that complemented a S. cerevisiae copper transport mutant, consistent with partial copper transport activity. Quantitative reverse transcription-polymerase chain reaction studies showed approximately normal levels of ATP7AG727R transcript in two patients’ fibroblasts compared to wild type controls, but Western blot analyses showed markedly reduced quantities of ATP7A protein, suggesting post-translational degradation. We confirmed the latter by comparing degradation rates of mutant and wild type ATP7A via cyclohexamide treatment of cultured fibroblasts; half-life of the G727R mutant was 2.9 hr and for the wild-type, 11.4 hr. We also documented a X-box binding protein 1 splice variant in G727R cells - known to be associated with the cellular misfolded protein response. Patient A, diagnosed 6 months of age, began treatment at 228 days (7.6 mos) of age. At his current age (2 years), his overall neurodevelopment remains at a 2 to 4 month level. In contrast, patients B and C were diagnosed in the neonatal period, began treatment within 25 days of age, and show near normal neurodevelopment at their current ages, 3 years (B), and 7 months (C). The poor clinical outcome in patient A with the same missense mutation as patients A and B with near normal oucomes, confirms the importance of early medical intervention in Menkes disease and highlights the critical potential benefit of newborn screening for this disorder. |
| Related Links | http://dx.doi.org/10.1016/j.ymgme.2008.06.015 |
| Starting Page | 174 |
| File Format | |
| ISSN | 10967206 |
| e-ISSN | 10967206 |
| Journal | Molecular genetics and metabolism |
| Issue Number | 3 |
| Volume Number | 95 |
| Language | English |
| Publisher Date | 2008-11-01 |
| Access Restriction | Open |
| Subject Keyword | Research in Higher Education |
| Content Type | Text |
| Resource Type | Article |
| Subject | Genetics Endocrinology, Diabetes and Metabolism Biochemistry Molecular Biology Endocrinology |
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