1. ¹Department of Medical Genetics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Sendai 980-8574, Japan
2. ²Division of Medical Genetics, Saitama Children's Medical Center, Saitama, Japan
3. ³Division of Medical Genetics, Kanagawa Children's Medical Center, Yokohama, Japan
4. ⁴Department of Pediatrics, Nagasaki University of Medicine, Nagasaki, Japan
5. ⁵Division of Clinical Genetics and Cytogenetics, Shizuoka Children's Hospital, Shizuoka, Japan
6. ⁶Division of Medical Genetics, Nagano Children's Hospital, Nagano, Japan
7. ⁷Department of Pediatrics, Sapporo Medical University, Sapporo, Japan
8. ⁸Okazaki Women's Junior College, Okazaki, Japan
9. ⁹Department of Medical Genetics, Kitasato University Graduate School of Medical Sciences, Sagamihara, Japan
10. ¹⁰Department of Pediatrics, Seirei Hamamatsu General Hospital, Hamamatsu, Japan
11. ¹¹Department of Cardiovascular Surgery, Tohoku University School of Medicine, Sendai, Japan
12. ¹²Department of Pediatrics, Osaka Medical College, Osaka, Japan
13. ¹³Department of Pediatrics, Jikei University Hospital, Tokyo, Japan
14. ¹⁴Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan
15. ¹⁵Department of Hematology and Oncology, Miyagi Children's Hospital, Sendai, Japan

Correspondence: Yoko Aoki, Department of Medical Genetics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Sendai 980-8574, Japan. Fax: +81-22-7178142. E-mail: aokiy@mail.tains.tohoku.ac.jp

Received 19 November 2004; Accepted 25 January 2005; Published online 15 April 2005.

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.