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Analysis of Mitochondrial DNA in Discordant Monozygotic Twins With Neurofibromatosis Type 1

Published online by Cambridge University Press:  21 February 2012

Anne Katrin Detjen
Affiliation:
Department of Neuropediatrics, Charité, University Medical Center, Berlin, Germany.
Sigrid Tinschert
Affiliation:
Institute of Clinical Genetics, Medical Faculty Carl Gustav Carus,Technology University Dresden, Dresden, Germany.
Dieter Kaufmann
Affiliation:
Department of Human Genetics, University Ulm, Ulm, Germany.
Bernd Algermissen
Affiliation:
Department of Laser Medicine, Krankenhaus Neukölln, Berlin, Germany.
Peter Nürnberg
Affiliation:
Cologne Center for Genomics and Institute for Genetics, University of Cologne, Cologne, Germany.
Markus Schuelke*
Affiliation:
Department of Neuropediatrics, Charité, University Medical Center, Berlin, Germany; Neuroscience Research Center, Charité, University Medical Center, Berlin, Germany. markus.schuelke@charite.de
*
*Address for correspondence: Markus Schuelke, Department of Neuropediatrics, Charité, Campus Virchow Klinikum, Augustenburger Platz 1,D-13353 Berlin, Germany.

Abstract

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Neurofibromatosis type 1 (NF1) is the most frequent neurocutaneous disorder with autosomal dominant inheritance. Phenotype variability is high ranging from merely several café-au-lait spots to malignant peripheral nerve sheath tumors or severe disfigurement through plexiform neurofibromas. Identification of genetic factors that modify the NF1 phenotype would contribute to the understanding of NF1 pathophysiology and improve patient counselling. As even monozygotic (MZ) twins with NF1 may differ phenotypically, we wondered whether these variations might be inherited in a non-Mendelian fashion. Mitochondrial DNA (mtDNA) is inherited extrachromosomally through the cytoplasm of the oocyte and often harbours heteroplasmic sequence variations. At the time of blastomere separation, these variants may be skewedly distributed and effect phenotypic differences. Because of their co-localization with the tumor suppressor protein neurofibromin, which is mutated in NF1, mitochondria were particular attractive candidates for investigation. MtDNA was extracted from nucleated blood cells of four pairs of discordant MZ twins with NF1 and from cutaneous neurofibromas of one twin pair. We sequenced the entire mitochondrial genome and determined the state of heteroplasmy by investigating a microsatellite region of the mitochondrial D-loop (D310-tract). The clinical diagnosis was confirmed in all patients by detection of pathogenic mutations in the NF1 gene. Monozygosity was verified by genotyping. However, we did not detect evidence for mtDNA sequence differences or for different degrees of heteroplasmy between individuals of the same twin pair. The phenotypic discordance of MZ twins with NF1 cannot be explained by skewed distribution of mtDNA mutations or polymorphisms.

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