This report describes juvenile myelomonocytic leukemia, PTPN11-related (JMML, PTPN11-related). The human gene
implicated in this disease is PTPN11, which encodes a protein-tyrosine phosphatase. This gene is also associated with Noonan syndrome 1 (OMIM:163950, FBhh0000040), Noonan syndrome with multiple lentigines 1 (OMIM:151100, FBhh0000041), and metachondromatosis (OMIM:156250). There is one high-scoring fly ortholog, csw , for which RNAi targeting constructs, alleles caused by insertional mutagenesis, and classical amorphic alleles have been generated.
A transgenic construct of the wild-type human Hsap\PTPN11 gene under the control of a heat-shock promoter has been introduced into flies. Partial heterologous rescue (functional complementation) has been demonstrated: rescue of some, but not all, phenotypes of Dmel\csw null mutants is observed.
A UAS construct of Dmel\csw bearing a mutation corresponding to a JMML PTPN11 mutation has been introduced into flies. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): E76K in the fly csw gene (corresponds to E76K in the human PTPN11 gene). This pathogenic variant produces dominant gain-of-function phenotypes in the fly, which recapitulates observations in human. GOF variants of PTPN11 implicated in JMML have also been used in flies to characterize the spacing effect for long-term memory induction. In addition to the variant described above, D61Y in the fly csw gene (corresponds to D61Y in the human PTPN11 gene) and T73I in the fly csw gene (corresponds to T73I in the human PTPN11 gene), were used in this study.
Animals homozygous for amorphic mutations of Dmel\csw die during larval and pupal stages. Germline clones in females result in maternal-effect lethality during during the embryonic stage; the embryos exhibit severe anatomical defects. Physical and genetic interactions of Dmel\csw have been described; see below and in the csw gene report.
[updated Aug. 2020 by FlyBase; FBrf0222196]
Many to one: 2 human to 1 Drosophila; the second human gene is PTPN6.