title: Comprehensive genetic analysis of overlapping syndromes of RAS/RAF/MEK/ERK pathway.
abstract: BACKGROUND
  Germline mutations in several members of RAS/RAF/MEK/ERK pathway cause clinically similar genetic disorders, including Noonan syndrome (NS), Costello syndrome (CS) and cardio-facio-cutaneous syndrome (CFC). Each of these syndromes has a wide spectrum of molecular etiology. The aim of the present study was to conduct a comprehensive genetic analysis of RAS/RAF/MEK/ERK pathway in these syndromes.
  
  
  METHODS
  Three patients with NS and two patients with CS/CFC were examined. Peripheral blood samples were collected from all patients as well as from 100 healthy Japanese volunteers. The protein phosphatase, non-receptor type II (PTPN11), KRAS, HRAS, NRAS, BRAF, RAF1, Son of Sevenless (SOS1) and MEK1genes were analyzed.
  
  
  RESULTS
  In a patient with a severe Noonan phenotype, a rare PTPN11 mutation was detected: A to G transition at position 172, causing an N58D substitution within the N-SH2 domain. In a CS/CFC patient no HRAS mutations were found, but a novel SOS1 missense mutation was found: A to G transition at position 473, causing a T158A substitution within domain of histone-like fold (HF).
  
  
  CONCLUSIONS
  A case mimicking CS with SOS1 T158A substitution, which has not been reported previously in CS, revealed the complex relationship between the genotype and phenotype of overlapping syndromes of the RAS/RAF/MEK/ERK pathway.
authors.affiliation: Department of Developmental Medical Sciences, Institute of International Health, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Munkhtuya
authors.initials: M
authors.lastname: Tumurkhuu
authors.forename: Makiko
authors.initials: M
authors.lastname: Saitoh
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sato
authors.forename: Kan
authors.initials: K
authors.lastname: Takahashi
authors.forename: Masakazu
authors.initials: M
authors.lastname: Mimaki
authors.forename: Junko
authors.initials: J
authors.lastname: Takita
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Takeshita
authors.forename: Takehiro
authors.initials: T
authors.lastname: Hama
authors.forename: Akira
authors.initials: A
authors.lastname: Oka
authors.forename: Masashi
authors.initials: M
authors.lastname: Mizuguchi
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D002648:Child; D056685:Costello Syndrome / Q000235:genetics*; D005145:Face / Q000002:abnormalities*; D005260:Female; D011905:Genes, ras / Q000235:genetics; D006330:Heart Defects, Congenital / Q000235:genetics*; D006801:Humans; D007223:Infant; D020935:MAP Kinase Signaling System / Q000235:genetics*; D008297:Male; D009154:Mutation; D009634:Noonan Syndrome / Q000235:genetics*; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D012868:Skin Abnormalities / Q000235:genetics*; D020664:Son of Sevenless Proteins / Q000235:genetics*; D013577:Syndrome; D018631:ras Proteins / Q000235:genetics
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D020664:Son of Sevenless Proteins; C516649:PTPN2 protein, human; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins