Abstract
We report on the clinical, molecular and biochemical findings of a patient with the rare event (<4.02 × 10−9 per generation) of coinciding de novo mutations in the nuclear PAX6 (c.1252–1267del16) and the mitochondrial mt.RNA Lys (8347A→G) genes. The boy suffers from exercise intolerance, ptosis, nystagmus, macular hypoplasia and anterior segment abnormalities evocative of Axenfeld–Rieger anomaly. The PAX6 mutation is predicted to cause haploinsufficiency. The novel mt.RNA Lys mutation is located close to the classic myoclonic epilepsy with ragged-red-fibers mutation, but the patient exhibits neither myoclonic epilepsy nor ragged-red-fibers. The degree of mutant mtDNA heteroplasmy, as determined by a very accurate pyrosequencing assay, varies between 31% (muscle) and 38% (fibroblasts). We discuss a potential effect of the PAX6 mutation on the mtDNA mutation rate.
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Acknowledgments
The authors thank the patient and his family for their participation in this study, Jan Jaroszewski, Anke Horn and Angelika Zwirner for expert clinical and technical assistance and Veronica van Heyningen, David FitzPatrick and Christine Gerstenfeld for critical discussions and valuable suggestions. This study was supported by the Deutsche Forschungsgemeinschaft (Grant SFB 577 TP B3 “Genetic variability of mitochondrial disorders” to MS) and the German Federal Ministry of Science and Education through the National Genome Research Network (Grant# 01GR0416 to P.N.).
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Brinckmann, A., Rüther, K., Williamson, K. et al. De novo double mutation in PAX6 and mtDNA tRNA Lys associated with atypical aniridia and mitochondrial disease. J Mol Med 85, 163–168 (2007). https://doi.org/10.1007/s00109-006-0112-y
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DOI: https://doi.org/10.1007/s00109-006-0112-y