Activating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome - Université de Rennes Access content directly
Journal Articles Human Mutation Year : 2015

Activating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome

Viviana Cordeddu
  • Function : Author
  • PersonId : 912915
Jiani C. Yin
  • Function : Author
Carl Virtanen
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Séverine Drunat
Francesca Lepri
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  • PersonId : 912909
Alessandro de Luca
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Cesare Rossi
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  • PersonId : 912912
Andrea Ciolfi
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Trevor J. Pugh
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Alessandro Bruselles
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James R. Priest
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Len A. Pennacchio
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Zhibin Lu
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Arnavaz Danesh
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Rene Quevedo
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Alaa Hamid
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Simone Martinelli
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Maria Gnazzo
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Paola Daniele
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Christina Lissewski
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Gianfranco Bocchinfuso
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Marketa Vlckova
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Eva Seemanova
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Cristina Digilio
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Martin Zenker
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  • PersonId : 888997
Giuseppe Zampino
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  • PersonId : 912933
Amy E. Roberts
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Bruce D. Gelb
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Benjamin G. Neel
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Marco Tartaglia
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  • PersonId : 912936

Abstract

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

Dates and versions

hal-01225504 , version 1 (06-11-2015)

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Viviana Cordeddu, Jiani C. Yin, Cecilia Gunnarsson, Carl Virtanen, Séverine Drunat, et al.. Activating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome. Human Mutation, 2015, 36 (11), pp.1080--1087. ⟨10.1002/humu.22834⟩. ⟨hal-01225504⟩
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