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  • A Corrigendum to this article was published on 01 February 2007

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Abstract

Noonan syndrome is a developmental disorder characterized by short stature, facial dysmorphia, congenital heart defects and skeletal anomalies1. Increased RAS-mitogen-activated protein kinase (MAPK) signaling due to PTPN11 and KRAS mutations causes 50% of cases of Noonan syndrome2,3,4,5,6. Here, we report that 22 of 129 individuals with Noonan syndrome without PTPN11 or KRAS mutation have missense mutations in SOS1, which encodes a RAS-specific guanine nucleotide exchange factor. SOS1 mutations cluster at codons encoding residues implicated in the maintenance of SOS1 in its autoinhibited form. In addition, ectopic expression of two Noonan syndrome–associated mutants induces enhanced RAS and ERK activation. The phenotype associated with SOS1 defects lies within the Noonan syndrome spectrum but is distinctive, with a high prevalence of ectodermal abnormalities but generally normal development and linear growth. Our findings implicate gain-of-function mutations in a RAS guanine nucleotide exchange factor in disease for the first time and define a new mechanism by which upregulation of the RAS pathway can profoundly change human development.

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Change history

  • 13 December 2006

    In the version of this article initially published online, the labels ‘expression’ in Figure 2 panels a, b and d are incorrect. The correct labels are ‘activation’. In addition, author Giuseppe Zampino should have affiliation 8 rather than affiliation 7. These errors have been corrected for all version of the article.

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Acknowledgements

We are indebted to the individuals and families who participated in the study, the physicians who referred the subjects and the Joint Genome Institute Production Sequencing Group. We thank J. Kuriyan and H. Sondermann for helpful discussions. This work was supported by Telethon-Italy (grant GGP04172) and the 'Programma di Collaborazione Italia-USA/Malattie Rare' (M.T.); US National Institutes of Health grants HL71207, HD01294 and HL074728 (B.D.G.) and CA55360 and CA28146 (D.B.-S.) and Italian Ministry of Health Grant RC 2006 (B.D.). Research conducted at the E.O. Lawrence Berkeley National Laboratory and the Joint Genome Institute was performed under Department of Energy contract DE-AC0378SF00098 at the University of California (L.A.P.).

Author information

Affiliations

  1. Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy.

    • Marco Tartaglia
    • , Valentina Fodale
    • , Simone Martinelli
    •  & Claudio Carta
  2. Genomics Division, MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.

    • Len A Pennacchio
    • , Wendy Schackwitz
    • , Anna Ustaszewska
    • , Joel Martin
    •  & James Bristow
  3. US Department of Energy Joint Genome Institute, 2800 Mitchell Drive, Walnut Creek, California 94598, USA.

    • Len A Pennacchio
    • , Wendy Schackwitz
    • , Joel Martin
    •  & James Bristow
  4. Department of Biochemistry, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.

    • Chen Zhao
    • , Kamlesh K Yadav
    •  & Dafna Bar-Sagi
  5. Istituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo della Sofferenza, San Giovanni Rotondo and CSS-Mendel Institute, Viale Regina Elena 261, 00198, Rome, Italy.

    • Anna Sarkozy
    • , Francesca Lepri
    • , Cinzia Neri
    •  & Bruno Dallapiccola
  6. Department of Experimental Medicine and Pathology, University La Sapienza, Viale Regina Elena 261, 00198, Rome, Italy.

    • Anna Sarkozy
    • , Francesca Lepri
    • , Cinzia Neri
    •  & Bruno Dallapiccola
  7. Center for Molecular Cardiology and Departments of Pediatrics and Human Genetics, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York 10029, USA.

    • Bhaswati Pandit
    • , Kimihiko Oishi
    •  & Bruce D Gelb
  8. Istituto di Clinica Pediatrica, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168, Rome, Italy.

    • Isabella Vasta
    •  & Giuseppe Zampino
  9. Royal Children's Hospital, Herston Road, Herston, Queensland 4029, Australia.

    • Kate Gibson
  10. Genetic Medicine Central California, 351 East Barstow #106, Fresno, California 93710, USA.

    • Cynthia J Curry
  11. Endocrinología Pediátrica, Hospital Materno-Infantil, Avida Arroyo de los Ángeles, 29011 Málaga, Spain.

    • Juan Pedro López Siguero
  12. Genetica Medica, Ospedale Bambino Gesù, Piazza S. Onofrio 4, 00165, Rome, Italy.

    • Maria Cristina Digilio

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Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Marco Tartaglia or Bruce D Gelb.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    Facial dysmorphia in SOS1-associated Noonan syndrome.

  2. 2.

    Supplementary Table 1

    Genotype-phenotype correlation

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DOI

https://doi.org/10.1038/ng1939

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