title: Tissue-specific differences in the proportion of mosaic large NF1 deletions are suggestive of a selective growth advantage of hematopoietic del(+/-) stem cells.
abstract: Type-2 NF1 deletions spanning 1.2 Mb are frequently of postzygotic origin and hence tend to be associated with mosaicism for normal cells and those harboring the deletion (del(+/-) cells). Eleven patients with mosaic type-2 deletions were investigated by FISH and high proportions (94-99%) of del(+/-) cells were detected both in whole blood and in isolated CD3+, CD14+, CD15+, and CD19+ leukocytes. Significantly lower proportions of del(+/-) cells (24-82%) were however noted in urine-derived epithelial cells. A patient harboring an atypical large NF1 deletion with nonrecurrent breakpoints was also found to have a much higher proportion of del(+/-) cells in blood (96%) than in urine (51%). The tissue-specific differences in the proportions of del(+/-) cells as well as the X chromosome inactivation (XCI) patterns observed in these mosaic patients suggest that the majority of the deletions had occurred before or during the preimplantation blastocyst stage before the onset of XCI. We postulate that hematopoietic del(+/-) stem cells present at an early developmental stage are characterized by a selective growth advantage over normal cells lacking the deletion, leading to a high proportion of del(+/-) cells in peripheral blood from the affected patients.
authors.affiliation: Institute of Human Genetics, University of Ulm, Albert-Einstein-Allee 11, Ulm, Germany.
authors.forename: Angelika C
authors.initials: AC
authors.lastname: Roehl
authors.forename: Tanja
authors.initials: T
authors.lastname: Mussotter
authors.forename: David N
authors.initials: DN
authors.lastname: Cooper
authors.forename: Lan
authors.initials: L
authors.lastname: Kluwe
authors.forename: Katharina
authors.initials: K
authors.lastname: Wimmer
authors.forename: Josef
authors.initials: J
authors.lastname: Högel
authors.forename: Marion
authors.initials: M
authors.lastname: Zetzmann
authors.forename: Julia
authors.initials: J
authors.lastname: Vogt
authors.forename: Victor-Felix
authors.initials: VF
authors.lastname: Mautner
authors.forename: Hildegard
authors.initials: H
authors.lastname: Kehrer-Sawatzki
mesh_terms: D000293:Adolescent; D000328:Adult; D002478:Cells, Cultured; D002648:Child; D002872:Chromosome Deletion; D041321:Chromosomes, Human, X / Q000235:genetics; D005260:Female; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D009456:Neurofibromatosis 1 / Q000235:genetics*; D025542:Neurofibromin 1 / Q000235:genetics*; D055815:Young Adult
chemical_list: D025542:Neurofibromin 1