Transcriptional hallmarks of noonan syndrome and noonan‐like syndrome with loose anagen hair

Giovanni Battista Ferrero,Giuseppe Zampino,Giuseppe Merla,Giuseppina Baldassarre,Daniela Cantarella,Davide Corà,Laura Mazzanti,Marco Tartaglia,Nicoletta Crescenzio,Gabriele Picco,Fabio Timeus,Cesare Rossi,Elisabetta Flex,Claudio Isella,Nicoletta Chiesa,Margherita Silengo,Enzo Medico

doi:10.1002/humu.22026

Abstract

Noonan syndrome (NS) is among the most common nonchromosomal disorders affecting development and growth. NS is genetically heterogeneous, being caused by germline mutations affecting various genes implicated in the RAS signaling network. This network transduces extracellular signals into intracellular biochemical and transcriptional responses controlling cell proliferation, differentiation, metabolism, and senescence. To explore the transcriptional consequences of NS-causing mutations, we performed global mRNA expression profiling on peripheral blood mononuclear cells obtained from 23 NS patients carrying heterozygous mutations in PTPN11 or SOS1. Gene expression profiling was also resolved in five subjects with Noonan-like syndrome with loose anagen hair (NS/LAH), a condition clinically related to NS and caused by an invariant mutation in SHOC2. Robust transcriptional signatures were found to specifically discriminate each of the three mutation groups from 21 age- and sex-matched controls. Despite the only partial overlap in terms of gene composition, the three signatures showed a notable concordance in terms of biological processes and regulatory circuits affected. These data establish expression profiling of peripheral blood mononuclear cells as a powerful tool to appreciate differential perturbations driven by germline mutations of transducers involved in RAS signaling and to dissect molecular mechanisms underlying NS and other RASopathies. Hum Mutat 33:703–709, 2012. © 2012 Wiley Periodicals, Inc.

Highlights

Dysregulation of RAS signaling has recently been recognized to underlie a group of clinically related disorders affecting development and growth [Schubbert et al, 2007; Tartaglia and Gelb, 2010; Tidyman and Rauen, 2009]
Transcriptome analysis is a key tool to explore biological complexity of human diseases. We applied this approach to RASopathies with the aim of finding molecular correlates of the mutational status in peripheral blood mononuclear cells (PBMCs), focusing on the two genes most frequently mutated in Noonan syndrome (NS), PTPN11, and SOS1, and on SHOC2, which has been recently discovered to cause Noonan-like syndrome with loose anagen hair (NS/LAH), a disorder with clinical overlap with the former [Cordeddu et al, 2009]
When the overall cohort of NS patients was subdivided on the basis of the genetic lesion in the three gene-specific subgroups, larger and more homogeneous signatures emerged despite the lower sizes of subgroups

Summary

Introduction

Dysregulation of RAS signaling has recently been recognized to underlie a group of clinically related disorders affecting development and growth [Schubbert et al, 2007; Tartaglia and Gelb, 2010; Tidyman and Rauen, 2009] Most of these conditions, which are collectively named as RASopathies, share facial dysmorphism, a wide spectrum of heart disease, reduced postnatal growth, variable cognitive defects, and susceptibility to certain malignancies. In contrast to what observed in NS, other RASopathies exhibit a relatively homogeneous phenotype that generally reflects an underlying genetic homogeneity This is the case of Noonanlike syndrome with loose anagen hair (NL/LAH), a rare condition with clinical features partially overlapping those occurring in NS [Mazzanti et al, 2003], and caused by the invariant c.4A>G missense change (p.Ser2Gly) in SHOC2 [Cordeddu et al, 2009], a scaffold protein with regulatory function that positively modulate RAS signaling [Matsunaga-Udagawa et al, 2010; Rodriguez-Viciana et al, 2006]. Log2Ratio expression data were clustered and visualized using the GEDAS software [Fu and Medico, 2007]

Results

Findings

Discussion