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 syndrome^{2, 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.

1. Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy.
2. Genomics Division, MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.
3. US Department of Energy Joint Genome Institute, 2800 Mitchell Drive, Walnut Creek, California 94598, USA.
4. Department of Biochemistry, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.
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.
6. Department of Experimental Medicine and Pathology, University La Sapienza, Viale Regina Elena 261, 00198, Rome, Italy.
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.
8. Istituto di Clinica Pediatrica, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168, Rome, Italy.
9. Royal Children's Hospital, Herston Road, Herston, Queensland 4029, Australia.
10. Genetic Medicine Central California, 351 East Barstow #106, Fresno, California 93710, USA.
11. Endocrinología Pediátrica, Hospital Materno-Infantil, Avida Arroyo de los Ángeles, 29011 Málaga, Spain.
12. Genetica Medica, Ospedale Bambino Gesù, Piazza S. Onofrio 4, 00165, Rome, Italy.

Correspondence to: Marco Tartaglia¹ e-mail: mtartaglia@iss.it

Correspondence to: Bruce D Gelb⁷ e-mail: bruce.gelb@mssm.edu

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