title: Transcriptional hallmarks of Noonan syndrome and Noonan-like syndrome with loose anagen hair.
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.
authors.affiliation: Department of Pediatrics, University of Torino Medical School, Torino, Italy.
authors.forename: Giovanni Battista
authors.initials: GB
authors.lastname: Ferrero
authors.forename: Gabriele
authors.initials: G
authors.lastname: Picco
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Baldassarre
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Flex
authors.forename: Claudio
authors.initials: C
authors.lastname: Isella
authors.forename: Daniela
authors.initials: D
authors.lastname: Cantarella
authors.forename: Davide
authors.initials: D
authors.lastname: Corà
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Chiesa
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Crescenzio
authors.forename: Fabio
authors.initials: F
authors.lastname: Timeus
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Merla
authors.forename: Laura
authors.initials: L
authors.lastname: Mazzanti
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zampino
authors.forename: Cesare
authors.initials: C
authors.lastname: Rossi
authors.forename: Margherita
authors.initials: M
authors.lastname: Silengo
authors.forename: Marco
authors.initials: M
authors.lastname: Tartaglia
authors.forename: Enzo
authors.initials: E
authors.lastname: Medico
mesh_terms: D016022:Case-Control Studies; D005260:Female; D020869:Gene Expression Profiling; D006101:Granuloma, Giant Cell; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000502:physiology; D008297:Male; D009154:Mutation; D009634:Noonan Syndrome / Q000235:genetics* / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics* / Q000378:metabolism; D020837:SOS1 Protein / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D018631:ras Proteins / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C112913:SHOC2 protein, human; D020837:SOS1 Protein; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D018631:ras Proteins