Phosphatase-defective LEOPARD syndrome mutations in PTPN11 gene have gain-of-function effects during Drosophila development.
Missense mutations in the PTPN11 gene, which encodes the protein tyrosine phosphatase SHP-2, cause clinically similar but distinctive disorders, LEOPARD (LS) and Noonan (NS) syndromes. The LS is an autosomal dominant disorder with pleomorphic developmental abnormalities including lentigines, cardiac defects, short stature and deafness. Biochemical analyses indicated that LS alleles engender loss-of-function (LOF) effects, while NS mutations result in gain-of-function (GOF). These biochemical findings lead to an enigma that how PTPN11 mutations with opposite effects on function result in disorders that are so similar. To study the developmental effects of the commonest LS PTPN11 alleles (Y279C and T468M), we generated LS transgenic fruitflies using corkscrew (csw), the Drosophila orthologue of PTPN11. Ubiquitous expression of the LS csw mutant alleles resulted in ectopic wing veins and, for the Y279C allele, rough eyes with increased R7 photoreceptor numbers. These were GOF phenotypes mediated by increased RAS/MAPK signaling and requiring the LS mutant's residual phosphatase activity. Our findings provide the first evidence that LS mutant alleles have GOF developmental effects despite reduced phosphatase activity, providing a rationale for how PTPN11 mutations with GOF and LOF produce similar but distinctive syndromes.
Oishi
Kimihiko
K
Department of Pediatrics and the Center for Molecular Cardiology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA. kimihiko.oishi@mssm.edu
Zhang
Hui
H
Gault
William J
WJ
Wang
Cindy J
CJ
Tan
Cheryl C
CC
Kim
In-Kyong
IK
Ying
Huiwen
H
Rahman
Tabassum
T
Pica
Natalie
N
Tartaglia
Marco
M
Mlodzik
Marek
M
Gelb
Bruce D
BD
D000818:Animals; D030801:Animals, Genetically Modified; D004330:Drosophila / Q000033:anatomy & histology / Q000201:enzymology / Q000235:genetics* / Q000254:growth & development*; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D005123:Eye / Q000033:anatomy & histology / Q000254:growth & development / Q000378:metabolism; D006801:Humans; D044542:LEOPARD Syndrome / Q000201:enzymology* / Q000235:genetics; D020125:Mutation, Missense; D009634:Noonan Syndrome / Q000201:enzymology / Q000235:genetics; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014921:Wings, Animal / Q000033:anatomy & histology / Q000254:growth & development / Q000378:metabolism
D029721:Drosophila Proteins; C098692:Csw protein, Drosophila; D054558:Protein Tyrosine Phosphatases, Non-Receptor