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

Viviana Cordeddu , Jiani C. Yin , Cecilia Gunnarsson (1) , Carl Virtanen , Séverine Drunat (2) , Francesca Lepri (3) , Alessandro de Luca , Cesare Rossi (4) , Andrea Ciolfi , Trevor J. Pugh , Alessandro Bruselles , James R. Priest , Len A. Pennacchio , Zhibin Lu , Arnavaz Danesh , Rene Quevedo , Alaa Hamid , Simone Martinelli , Francesca Pantaleoni (5) , Maria Gnazzo , Paola Daniele , Christina Lissewski , Gianfranco Bocchinfuso , Lorenzo Stella (6) , Sylvie Odent (7, 8) , Nicole Philip (9) , Laurence Faivre (10) , Marketa Vlckova , Eva Seemanova , Cristina Digilio , Martin Zenker (11) , Giuseppe Zampino (12) , Alain Verloes (13, 2) , Bruno Dallapiccola (14) , Amy E. Roberts , Hélène Cavé (15) , Bruce D. Gelb , Benjamin G. Neel , Marco Tartaglia (5)

1 LIU - Linköping University
2 Département de génétique
3 Laboratorio Mendel
4 UO Genetica Medica
5 Ematologia, Oncologia e Medicina Molecolare
6 Dipartimento di Scienze e Tecnologie Chimiche
7 IGDR - Institut de Génétique et Développement de Rennes
8 CHU Pontchaillou [Rennes]
9 Service de Génétique
10 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
11 Institute of Human Genetics
12 Clinica Pediatrica
13 Physiopathologie et neuroprotection des atteintes du cerveau en développement
14 Medical Genetics and Pediatric Cardiology
15 Département de génétique [Robert Debré]

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

Keywords: genotype-phenotype correlations; Noonan syndrome; RAS signaling; SOS2

Domains: Life Sciences [q-bio]

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⟩