Functional Dysregulation of CDC42 Causes Diverse Developmental Phenotypes

University of Washington Center for Mendelian Genomics

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)309-320
Number of pages12
JournalAmerican Journal of Human Genetics
Volume102
Issue number2
DOIs
Publication statusPublished - Feb 1 2018

Fingerprint

Phenotype
Mutation
Noonan Syndrome
Exome
Monomeric GTP-Binding Proteins
GTP Phosphohydrolases
Genetic Association Studies
Computer Simulation
Growth
Genes
In Vitro Techniques

Cite this

Functional Dysregulation of CDC42 Causes Diverse Developmental Phenotypes. / University of Washington Center for Mendelian Genomics.

In: American Journal of Human Genetics, Vol. 102, No. 2, 01.02.2018, p. 309-320.

Research output: Contribution to journalArticle

University of Washington Center for Mendelian Genomics. / Functional Dysregulation of CDC42 Causes Diverse Developmental Phenotypes. In: American Journal of Human Genetics. 2018 ; Vol. 102, No. 2. pp. 309-320.
@article{a170bb067f97406488d3498daf57775c,
title = "Functional Dysregulation of CDC42 Causes Diverse Developmental Phenotypes",
abstract = "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.",
author = "{University of Washington Center for Mendelian Genomics} and Simone Martinelli and Krumbach, {Oliver H F} and Francesca Pantaleoni and Simona Coppola and Ehsan Amin and Luca Pannone and Kazem Nouri and Luciapia Farina and Radovan Dvorsky and Francesca Lepri and Marcel Buchholzer and Raphael Konopatzki and Laurence Walsh and Katelyn Payne and Pierpont, {Mary Ella} and Vergano, {Samantha Schrier} and Langley, {Katherine G} and Douglas Larsen and Farwell, {Kelly D} and Sha Tang and Cameron Mroske and Ivan Gallotta and {Di Schiavi}, Elia and {Della Monica}, Matteo and Licia Lugli and Cesare Rossi and Marco Seri and Guido Cocchi and Lindsay Henderson and Berivan Baskin and Mari{\"e}lle Alders and Roberto Mendoza-Londono and Lucie Dupuis and Nickerson, {Deborah A} and Chong, {Jessica X} and Naomi Meeks and Kathleen Brown and Tahnee Causey and Cho, {Megan T} and Stephanie Demuth and Digilio, {Maria Cristina} and Gelb, {Bruce D} and Bamshad, {Michael J} and Martin Zenker and Ahmadian, {Mohammad Reza} and Hennekam, {Raoul C} and Marco Tartaglia and Mirzaa, {Ghayda M}",
note = "Copyright {\circledC} 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.",
year = "2018",
month = "2",
day = "1",
doi = "10.1016/j.ajhg.2017.12.015",
language = "English",
volume = "102",
pages = "309--320",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "2",

}

TY - JOUR

T1 - Functional Dysregulation of CDC42 Causes Diverse Developmental Phenotypes

AU - University of Washington Center for Mendelian Genomics

AU - Martinelli, Simone

AU - Krumbach, Oliver H F

AU - Pantaleoni, Francesca

AU - Coppola, Simona

AU - Amin, Ehsan

AU - Pannone, Luca

AU - Nouri, Kazem

AU - Farina, Luciapia

AU - Dvorsky, Radovan

AU - Lepri, Francesca

AU - Buchholzer, Marcel

AU - Konopatzki, Raphael

AU - Walsh, Laurence

AU - Payne, Katelyn

AU - Pierpont, Mary Ella

AU - Vergano, Samantha Schrier

AU - Langley, Katherine G

AU - Larsen, Douglas

AU - Farwell, Kelly D

AU - Tang, Sha

AU - Mroske, Cameron

AU - Gallotta, Ivan

AU - Di Schiavi, Elia

AU - Della Monica, Matteo

AU - Lugli, Licia

AU - Rossi, Cesare

AU - Seri, Marco

AU - Cocchi, Guido

AU - Henderson, Lindsay

AU - Baskin, Berivan

AU - Alders, Mariëlle

AU - Mendoza-Londono, Roberto

AU - Dupuis, Lucie

AU - Nickerson, Deborah A

AU - Chong, Jessica X

AU - Meeks, Naomi

AU - Brown, Kathleen

AU - Causey, Tahnee

AU - Cho, Megan T

AU - Demuth, Stephanie

AU - Digilio, Maria Cristina

AU - Gelb, Bruce D

AU - Bamshad, Michael J

AU - Zenker, Martin

AU - Ahmadian, Mohammad Reza

AU - Hennekam, Raoul C

AU - Tartaglia, Marco

AU - Mirzaa, Ghayda M

N1 - Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

PY - 2018/2/1

Y1 - 2018/2/1

N2 - 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.

AB - 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.

U2 - 10.1016/j.ajhg.2017.12.015

DO - 10.1016/j.ajhg.2017.12.015

M3 - Article

VL - 102

SP - 309

EP - 320

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 2

ER -