Abstract
Noonan syndrome (NS) is characterized by short stature, characteristic facial features, and heart defects. Recently, missense mutations of PTPN11, the gene encoding protein tyrosine phosphatase (PTP) SHP-2, were identified in patients with NS. Further, somatic mutations in PTPN11 were detected in childhood leukemia. Recent studies showed that the phosphatase activities of five mutations identified in NS and juvenile myelomonocytic leukemia (JMML) were increased. However, the functional properties of the other mutations remain unidentified. In this study, in order to clarify the differences between the mutations identified in NS and leukemia, we examined the phosphatase activity of 14 mutants of SHP-2. We identified nine mutations, including a novel F71I mutation, in 16 of 41 NS patients and two mutations, including a novel G503V mutation, in three of 29 patients with leukemia. Immune complex phosphatase assays of individual mutants transfected in COS7 cells showed that ten mutants identified in NS and four mutants in leukemia showed 1.4-fold to 12.7-fold increased activation compared with wild-type SHP-2. These results suggest that the pathogenesis of NS and leukemia is associated with enhanced phosphatase activity of mutant SHP-2. A comparison of the phosphatase activity in each mutant and a review of previously reported cases showed that high phosphatase activity observed in mutations at codons 61, 71, 72, and 76 was significantly associated with leukemogenesis.
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Acknowledgements
The authors thank the patients and their families who participated in this study and doctors who referred the cases. We are grateful to Dr. Takashi Matozaki, Gunma University, for supplying pcDNA-HAERK2 plasmid and anti-HA antibody, and Dr. Jun-ichi Miyazaki, Osaka University, for supplying the pCAGGS expression vector. We thank Kumi Kato, Dr. Xue Yang, and Dr. Yoshio Takahashi for their technical assistance. This work was supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan (No.15790172) and the Uehara Memorial Foundation Grant-in-Aid for Scientific Research to YA.
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Niihori, T., Aoki, Y., Ohashi, H. et al. Functional analysis of PTPN11/SHP-2 mutants identified in Noonan syndrome and childhood leukemia. J Hum Genet 50, 192–202 (2005). https://doi.org/10.1007/s10038-005-0239-7
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DOI: https://doi.org/10.1007/s10038-005-0239-7
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