title: Functional analysis of PTPN11/SHP-2 mutants identified in Noonan syndrome and childhood leukemia.
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.
authors.affiliation: Department of Medical Genetics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Sendai, 980-8574, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Niihori
authors.affiliation: Department of Medical Genetics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Sendai, 980-8574, Japan. aokiy@mail.tains.tohoku.ac.jp.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Aoki
authors.affiliation: Division of Medical Genetics, Saitama Children's Medical Center, Saitama, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Ohashi
authors.affiliation: Division of Medical Genetics, Kanagawa Children's Medical Center, Yokohama, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kurosawa
authors.affiliation: Department of Pediatrics, Nagasaki University of Medicine, Nagasaki, Japan.
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Kondoh
authors.affiliation: Division of Clinical Genetics and Cytogenetics, Shizuoka Children's Hospital, Shizuoka, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ishikiriyama
authors.affiliation: Division of Medical Genetics, Nagano Children's Hospital, Nagano, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawame
authors.affiliation: Department of Pediatrics, Sapporo Medical University, Sapporo, Japan.
authors.forename: Hotaka
authors.initials: H
authors.lastname: Kamasaki
authors.affiliation: Okazaki Women's Junior College, Okazaki, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Yamanaka
authors.affiliation: Department of Medical Genetics, Kitasato University Graduate School of Medical Sciences, Sagamihara, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Takada
authors.affiliation: Department of Pediatrics, Seirei Hamamatsu General Hospital, Hamamatsu, Japan.
authors.forename: Kimio
authors.initials: K
authors.lastname: Nishio
authors.affiliation: Department of Cardiovascular Surgery, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sakurai
authors.affiliation: Department of Pediatrics, Osaka Medical College, Osaka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tamai
authors.affiliation: Department of Pediatrics, Jikei University Hospital, Tokyo, Japan.
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Nagashima
authors.affiliation: Department of Medical Genetics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Sendai, 980-8574, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Department of Medical Genetics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Sendai, 980-8574, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Kure
authors.affiliation: Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Fujii
authors.affiliation: Department of Hematology and Oncology, Miyagi Children's Hospital, Sendai, Japan.
authors.forename: Masue
authors.initials: M
authors.lastname: Imaizumi
authors.affiliation: Department of Medical Genetics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Sendai, 980-8574, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Matsubara
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins; D007951:Leukemia, Myeloid / Q000145:classification / Q000235:genetics*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009634:Noonan Syndrome / Q000201:enzymology / Q000235:genetics*; D010641:Phenotype; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D018909:src Homology Domains
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D020928:Mitogen-Activated Protein Kinases; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases