@article {543,
	title = {Functional Dysregulation of CDC42 Causes Diverse Developmental Phenotypes.},
	journal = {Am J Hum Genet},
	volume = {102},
	year = {2018},
	month = {2018 Feb 01},
	pages = {309-320},
	abstract = {<p>Exome sequencing has markedly enhanced the discovery of genes implicated in Mendelian disorders, particularly for individuals in whom a known clinical entity could not be assigned. This has led to the recognition that phenotypic heterogeneity resulting from allelic mutations occurs more commonly than previously appreciated. Here, we report that missense variants in CDC42, a gene encoding a small GTPase functioning as an intracellular signaling node, underlie a clinically heterogeneous group of phenotypes characterized by variable growth dysregulation, facial dysmorphism, and neurodevelopmental, immunological, and hematological anomalies, including a phenotype resembling Noonan syndrome, a developmental disorder caused by dysregulated RAS signaling. In silico, in~vitro, and in~vivo analyses demonstrate that mutations variably perturb CDC42 function by altering the switch between the active and inactive states of the GTPase and/or affecting CDC42 interaction with effectors, and differentially disturb cellular and developmental processes. These findings reveal the remarkably variable impact that dominantly acting CDC42 mutations have on cell function and development, creating challenges in syndrome definition, and exemplify the importance of functional profiling for syndrome recognition and delineation.</p>},
	issn = {1537-6605},
	doi = {10.1016/j.ajhg.2017.12.015},
	author = {Martinelli, Simone and Krumbach, Oliver H F and Pantaleoni, Francesca and Coppola, Simona and Amin, Ehsan and Pannone, Luca and Nouri, Kazem and Farina, Luciapia and Dvorsky, Radovan and Lepri, Francesca and Buchholzer, Marcel and Konopatzki, Raphael and Walsh, Laurence and Payne, Katelyn and Pierpont, Mary Ella and Vergano, Samantha Schrier and Langley, Katherine G and Larsen, Douglas and Farwell, Kelly D and Tang, Sha and Mroske, Cameron and Gallotta, Ivan and Di Schiavi, Elia and Della Monica, Matteo and Lugli, Licia and Rossi, Cesare and Seri, Marco and Cocchi, Guido and Henderson, Lindsay and Baskin, Berivan and Alders, Marielle and Mendoza-Londono, Roberto and Dupuis, Lucie and Nickerson, Deborah A and Chong, Jessica X and Meeks, Naomi and Brown, Kathleen and Causey, Tahnee and Cho, Megan T and Demuth, Stephanie and Digilio, Maria Cristina and Gelb, Bruce D and Bamshad, Michael J and Zenker, Martin and Ahmadian, Mohammad Reza and Hennekam, Raoul C and Tartaglia, Marco and Mirzaa, Ghayda M}
}
@article {147,
	title = {Activating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome.},
	journal = {Hum Mutat},
	volume = {36},
	year = {2015},
	month = {2015 Nov},
	pages = {1080-7},
	abstract = {<p>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. </p>},
	keywords = {Adolescent, Adult, Alleles, Amino Acid Substitution, Child, DNA Mutational Analysis, Exome, Facies, Female, Genetic Association Studies, Genotype, Humans, Male, Models, Molecular, Mutation, Noonan Syndrome, Phenotype, Protein Conformation, Protein Interaction Domains and Motifs, Son of Sevenless Proteins, Young Adult},
	issn = {1098-1004},
	doi = {10.1002/humu.22834},
	author = {Cordeddu, Viviana and Yin, Jiani C and Gunnarsson, Cecilia and Virtanen, Carl and Drunat, S{\'e}verine and Lepri, Francesca and De Luca, Alessandro and Rossi, Cesare and Ciolfi, Andrea and Pugh, Trevor J and Bruselles, Alessandro and Priest, James R and Pennacchio, Len A and Lu, Zhibin and Danesh, Arnavaz and Quevedo, Rene and Hamid, Alaa and Martinelli, Simone and Pantaleoni, Francesca and Gnazzo, Maria and Daniele, Paola and Lissewski, Christina and Bocchinfuso, Gianfranco and Stella, Lorenzo and Odent, Sylvie and Philip, Nicole and Faivre, Laurence and Vlckova, Marketa and Seemanova, Eva and Digilio, Cristina and Zenker, Martin and Zampino, Giuseppe and Verloes, Alain and Dallapiccola, Bruno and Roberts, Amy E and Cav{\'e}, H{\'e}l{\`e}ne and Gelb, Bruce D and Neel, Benjamin G and Tartaglia, Marco}
}
