Functional Dysregulation of CDC42 Causes Diverse Developmental Phenotypes.

TitleFunctional Dysregulation of CDC42 Causes Diverse Developmental Phenotypes.
Publication TypeJournal Article
Year of Publication2018
AuthorsMartinelli, S, Krumbach, OHF, Pantaleoni, F, Coppola, S, Amin, E, Pannone, L, Nouri, K, Farina, L, Dvorsky, R, Lepri, F, Buchholzer, M, Konopatzki, R, Walsh, L, Payne, K, Pierpont, MElla, Vergano, SSchrier, Langley, KG, Larsen, D, Farwell, KD, Tang, S, Mroske, C, Gallotta, I, Di Schiavi, E, Monica, MDella, Lugli, L, Rossi, C, Seri, M, Cocchi, G, Henderson, L, Baskin, B, Alders, M, Mendoza-Londono, R, Dupuis, L, Nickerson, DA, Chong, JX, Meeks, N, Brown, K, Causey, T, Cho, MT, Demuth, S, Digilio, MCristina, Gelb, BD, Bamshad, MJ, Zenker, M, Ahmadian, MReza, Hennekam, RC, Tartaglia, M, Mirzaa, GM
Corporate AuthorsUniversity of Washington Center for Mendelian Genomics
JournalAm J Hum Genet
Date Published2018 Feb 01

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.

Alternate JournalAm. J. Hum. Genet.
PubMed ID29394990
PubMed Central IDPMC5985417
Grant ListUM1 HL098162 / HL / NHLBI NIH HHS / United States
U54 HG006493 / HG / NHGRI NIH HHS / United States
UM1 HL098123 / HL / NHLBI NIH HHS / United States
P40 OD010440 / OD / NIH HHS / United States
U01 HL131003 / HL / NHLBI NIH HHS / United States
K08 NS092898 / NS / NINDS NIH HHS / United States
UM1 HL128761 / HL / NHLBI NIH HHS / United States
UM1 HG006493 / HG / NHGRI NIH HHS / United States
UM1 HL128711 / HL / NHLBI NIH HHS / United States
UM1 HL098147 / HL / NHLBI NIH HHS / United States