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Molecular dissection of isolated disease features in mosaic neurofibromatosis type 1

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Abstract
Elucidation of the biological framework underlying the development of neurofibromatosis type I (NFI)-related symptoms has proved to be difficult. Complicating factors include the large size of the NFI gene, the presence of several NFI pseudogenes, the complex interactions between cell types, and the NFI-haploinsufficient state of all cells in the body. Here, we investigate three patients with distinct NFI-associated clinical manifestations (neurofibromas only, pigmentary changes only, and association of both symptoms). For each patient, various tissues and cell types were tested with comprehensive and quantitative assays capable of detecting low-percentage NFI mutations. This approach confirmed the biallelic NF1 inactivation in Schwann cells in neurofibromas and, for the first time, demonstrated biallelic NF1 inactivation in melanocytes in NF1-related cafe-au-lait macules. Interestingly, both disease features arise even within a background of predominantly NF1 wild-type cells. Together, the data provide molecular evidence that (1) the distinct clinical picture of the patients is due to mosaicism for the NF1 mutation and (2) the mosaic phenotype reflects the embryonic timing and, accordingly, the neural crest-derived cell type involved in the somatic W I mutation. The study of the affected cell types provides important insight into developmental concepts underlying particular NF1-related disease features and opens avenues for improved diagnosis and genetic counseling of individuals with mosaic NFI.

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Chicago
Maertens, Ophélia, Sofie De Schepper, Jo Vandesompele, Hilde Brems, Ine Heyns, Sandra Janssens, Franki Speleman, Eric Legius, and Ludwine Messiaen. 2007. “Molecular Dissection of Isolated Disease Features in Mosaic Neurofibromatosis Type 1.” American Journal of Human Genetics 81 (2): 243–251.
APA
Maertens, Ophélia, De Schepper, S., Vandesompele, J., Brems, H., Heyns, I., Janssens, S., Speleman, F., et al. (2007). Molecular dissection of isolated disease features in mosaic neurofibromatosis type 1. AMERICAN JOURNAL OF HUMAN GENETICS, 81(2), 243–251.
Vancouver
1.
Maertens O, De Schepper S, Vandesompele J, Brems H, Heyns I, Janssens S, et al. Molecular dissection of isolated disease features in mosaic neurofibromatosis type 1. AMERICAN JOURNAL OF HUMAN GENETICS. UNIV CHICAGO PRESS; 2007;81(2):243–51.
MLA
Maertens, Ophélia, Sofie De Schepper, Jo Vandesompele, et al. “Molecular Dissection of Isolated Disease Features in Mosaic Neurofibromatosis Type 1.” AMERICAN JOURNAL OF HUMAN GENETICS 81.2 (2007): 243–251. Print.
@article{390273,
  abstract     = {Elucidation of the biological framework underlying the development of neurofibromatosis type I (NFI)-related symptoms has proved to be difficult. Complicating factors include the large size of the NFI gene, the presence of several NFI pseudogenes, the complex interactions between cell types, and the NFI-haploinsufficient state of all cells in the body. Here, we investigate three patients with distinct NFI-associated clinical manifestations (neurofibromas only, pigmentary changes only, and association of both symptoms). For each patient, various tissues and cell types were tested with comprehensive and quantitative assays capable of detecting low-percentage NFI mutations. This approach confirmed the biallelic NF1 inactivation in Schwann cells in neurofibromas and, for the first time, demonstrated biallelic NF1 inactivation in melanocytes in NF1-related cafe-au-lait macules. Interestingly, both disease features arise even within a background of predominantly NF1 wild-type cells. Together, the data provide molecular evidence that (1) the distinct clinical picture of the patients is due to mosaicism for the NF1 mutation and (2) the mosaic phenotype reflects the embryonic timing and, accordingly, the neural crest-derived cell type involved in the somatic W I mutation. The study of the affected cell types provides important insight into developmental concepts underlying particular NF1-related disease features and opens avenues for improved diagnosis and genetic counseling of individuals with mosaic NFI.},
  author       = {Maertens, Oph{\'e}lia and De Schepper, Sofie and Vandesompele, Jo and Brems, Hilde and Heyns, Ine and Janssens, Sandra and Speleman, Franki and Legius, Eric and Messiaen, Ludwine},
  issn         = {0002-9297},
  journal      = {AMERICAN JOURNAL OF HUMAN GENETICS},
  language     = {eng},
  number       = {2},
  pages        = {243--251},
  publisher    = {UNIV CHICAGO PRESS},
  title        = {Molecular dissection of isolated disease features in mosaic neurofibromatosis type 1},
  url          = {http://dx.doi.org/10.1086/519562},
  volume       = {81},
  year         = {2007},
}

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