TY - JOUR
T1 - Opposite modulation of RAC1 by mutations in TRIO is associated with distinct, domain specific neurodevelopmental disorders
AU - Barbosa, Sónia
AU - Greville-Heygate, Stephanie
AU - Bonnet, Maxime
AU - Godwin, Annie Louise
AU - Fagotto-Kaufmann, Christine
AU - Kajava, Andrey V.
AU - Laouteouet, Damien
AU - Mawby, Rebecca
AU - Wai, Htoo Aung
AU - Dingemans, Alexander
AU - De Vries, Bert
AU - Willems, Marjorlaine
AU - Capri, Yline
AU - Mehta, Sarju G.
AU - Cox, Helen
AU - Goudie, David
AU - Vansenne, Fleur
AU - Turnpenny, Peter
AU - Vincent, Marie
AU - Lesca, Gaëtan
AU - Hertecant, Jozef
AU - Rodriguez, Diana
AU - Marion, Gérard
AU - Putoux, Audrey
AU - Ramsey, Keri
AU - Cantagrel, Vincent
AU - Banka, Siddharth
AU - Sarkar, Ajoy
AU - Steeves, Marcie
AU - Parker, Michael
AU - Clement, Emma
AU - Moutton, Sébastien
AU - Tran-Mau-Them, Frédéric
AU - Piton, Amélie
AU - Guille, Matt
AU - Debant, Anne
AU - Schmidt, Susanne
AU - Baralle, Diana
PY - 2020/3/5
Y1 - 2020/3/5
N2 - The Rho-guanine nucleotide exchange factor (RhoGEF) TRIO acts as a key regulator of neuronal migration, axonal outgrowth, axon guidance, and synaptogenesis by activating the GTPase RAC1 and modulating actin cytoskeleton remodeling. Pathogenic variants in TRIO are associated with neurodevelopmental diseases, including intellectual disability (ID) and autism spectrum disorders (ASD). Here, we report the largest international cohort of 24 individuals with confirmed pathogenic missense or nonsense variants in TRIO. The nonsense mutations are spread along the TRIO sequence, and affected individuals show variable neurodevelopmental phenotypes. In contrast, missense variants cluster into two mutational hotspots in the TRIO sequence, one in the seventh spectrin repeat and one in the RAC1-activating GEFD1. Although all individuals in this cohort present with developmental delay and a neuro-behavioral phenotype, individuals with a pathogenic variant in the seventh spectrin repeat have a more severe ID associated with macrocephaly than do most individuals with GEFD1 variants, who display milder ID and microcephaly. Functional studies show that the spectrin and GEFD1 variants cause a TRIO-mediated hyper- or hypo-activation of RAC1, respectively, and we observe a striking correlation between RAC1 activation levels and the head size of the affected individuals. In addition, truncations in TRIO GEFD1 in the vertebrate model X. tropicalis induce defects that are concordant with the human phenotype. This work demonstrates distinct clinical and molecular disorders clustering in the GEFD1 and seventh spectrin repeat domains and highlights the importance of tight control of TRIO-RAC1 signaling in neuronal development.
AB - The Rho-guanine nucleotide exchange factor (RhoGEF) TRIO acts as a key regulator of neuronal migration, axonal outgrowth, axon guidance, and synaptogenesis by activating the GTPase RAC1 and modulating actin cytoskeleton remodeling. Pathogenic variants in TRIO are associated with neurodevelopmental diseases, including intellectual disability (ID) and autism spectrum disorders (ASD). Here, we report the largest international cohort of 24 individuals with confirmed pathogenic missense or nonsense variants in TRIO. The nonsense mutations are spread along the TRIO sequence, and affected individuals show variable neurodevelopmental phenotypes. In contrast, missense variants cluster into two mutational hotspots in the TRIO sequence, one in the seventh spectrin repeat and one in the RAC1-activating GEFD1. Although all individuals in this cohort present with developmental delay and a neuro-behavioral phenotype, individuals with a pathogenic variant in the seventh spectrin repeat have a more severe ID associated with macrocephaly than do most individuals with GEFD1 variants, who display milder ID and microcephaly. Functional studies show that the spectrin and GEFD1 variants cause a TRIO-mediated hyper- or hypo-activation of RAC1, respectively, and we observe a striking correlation between RAC1 activation levels and the head size of the affected individuals. In addition, truncations in TRIO GEFD1 in the vertebrate model X. tropicalis induce defects that are concordant with the human phenotype. This work demonstrates distinct clinical and molecular disorders clustering in the GEFD1 and seventh spectrin repeat domains and highlights the importance of tight control of TRIO-RAC1 signaling in neuronal development.
KW - intellectual disability
KW - microcephaly
KW - macrocephaly
KW - autism
KW - RCUK
KW - BBSRC
KW - BB/R014841/1
U2 - 10.1016/j.ajhg.2020.01.018
DO - 10.1016/j.ajhg.2020.01.018
M3 - Article
SN - 0002-9297
VL - 106
SP - 338
EP - 355
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 3
ER -