The lethal prune/Killer-of-prune interaction of Drosophila causes a syndrome resembling human neurofibromatosis (NF1).
The eye color mutant prune (pn) of Drosophila melanogaster shows a lethal interaction with the Killer-of-prune (K-pn) allele of the abnormal wing disc (awd) locus. The awd gene is the Drosophila homologue of the mammalian tumor metastasis gene nm23, and it has been postulated that pn encodes a protein with similarity to a GAP, a GTPase-activating protein. Such GAPs potentially control Ras-like proteins, which are important molecular switches. However, there is only a low sequence homology with the genes for human GAP and neurofibromatosis (NF1), and with yeast IRA1 and IRA2, and there is no evidence for the functional significance of this homologization. I now show that pn mutations lower the concentrations of larval pteridines, and that this phenomenon is enhanced by two orders of magnitude by the lethal interaction between pn and awdK-pn. These gradual effects on the pteridin concentrations indicate a corresponding drop of the pools of free GTP, and favor the involvement of GTP-binding proteins. In addition, cytology reveals a considerable hypertrophy of the neuroglia and the perineurium of the larval brain. Furthermore, the lymph glands of the larvae are highly abnormal and form melanotic (pseudo)tumors upon ageing of the larvae. These pseudotumors consist predominantly of lamellocytes which are part of the cellular defence system of Drosophila. These observations most likely indicate hyperactivity of a Ras-like protein which becomes manifest in cell types equivalent to the cell types affected by human neurofibromatosis (NF1). Thus, it is very suggestive to regard the synthetic lethal system prune/Killer-of-prune as the Drosophila model for human neurofibromatosis.
Hackstein
J H
JH
Department of Microbiology, Catholic University of Nijmegen, The Netherlands.
D000596:Amino Acids / Q000032:analysis; D000818:Animals; D004331:Drosophila melanogaster / Q000235:genetics* / Q000378:metabolism; D005804:Genes, Lethal; D007814:Larva / Q000378:metabolism / Q000648:ultrastructure; D017253:Neurofibromatoses / Q000235:genetics*; D011621:Pteridines / Q000032:analysis
D000596:Amino Acids; D011621:Pteridines