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Activating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome
Ist Super Sanita, Italy; University of G dAnnunzio, Italy.
University of Toronto, Canada; University of Toronto, Canada.
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics. Linköping University, Faculty of Medicine and Health Sciences.
University of Toronto, Canada; University of Toronto, Canada.
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2015 (English)In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 36, no 11, 1080-1087 p.Article in journal (Refereed) Published
Abstract [en]

The RASopathies constitute a family of autosomal-dominant disorders whose major features include facial dysmorphism, cardiac defects, reduced postnatal growth, variable cognitive deficits, ectodermal and skeletal anomalies, and susceptibility to certain malignancies. Noonan syndrome (NS), the commonest RASopathy, is genetically heterogeneous and caused by functional dysregulation of signal transducers and regulatory proteins with roles in the RAS/extracellular signal-regulated kinase (ERK) signal transduction pathway. Mutations in known disease genes account for approximately 80% of affected individuals. Here, we report that missense mutations altering Son of Sevenless, Drosophila, homolog 2 (SOS2), which encodes a RAS guanine nucleotide exchange factor, occur in a small percentage of subjects with NS. Four missense mutations were identified in five unrelated sporadic cases and families transmitting NS. Disease-causing mutations affected three conserved residues located in the Dbl homology (DH) domain, of which two are directly involved in the intramolecular binding network maintaining SOS2 in its autoinhibited conformation. All mutations were found to promote enhanced signaling from RAS to ERK. Similar to NS-causing SOS1 mutations, the phenotype associated with SOS2 defects is characterized by normal development and growth, as well as marked ectodermal involvement. Unlike SOS1 mutations, however, those in SOS2 are restricted to the DH domain.

Place, publisher, year, edition, pages
WILEY-BLACKWELL , 2015. Vol. 36, no 11, 1080-1087 p.
Keyword [en]
genotype-phenotype correlations; Noonan syndrome; RAS signaling; SOS2
National Category
Clinical Medicine
URN: urn:nbn:se:liu:diva-122516DOI: 10.1002/humu.22834ISI: 000362991400011PubMedID: 26173643OAI: diva2:868053

Funding Agencies|National Institutes of Health [R01 HL071207, R01 HL0832732, U01 DE020060, R01 HG003988, U54 HG006997, U54 HG006504]; Telethon-Italy [GGP13107]; AIRC [IG 13360]; Ministry of Health [RF-2011-02349938]; Princess Margaret Cancer Foundation; Ontario Ministry of Health and Long Term Care; CIHR CGS-D

Available from: 2015-11-09 Created: 2015-11-06 Last updated: 2015-11-09

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Gunnarsson, Cecilia
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Division of Cell BiologyDepartment of Clinical Pathology and Clinical GeneticsFaculty of Medicine and Health Sciences
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