TY - JOUR
T1 - RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes
AU - Reijnders, Margot R. F.
AU - Ansor, Nurhuda M.
AU - Kousi, Maria
AU - Yue, Wyatt W.
AU - Tan, Perciliz L.
AU - Clarkson, Katie
AU - Clayton-Smith, Jill
AU - Corning, Ken
AU - Jones, Julie R.
AU - Lam, Wayne W. K.
AU - Mancini, Grazia M. S.
AU - Marcelis, Carlo
AU - Mohammed, Shehla
AU - Pfundt, Rolph
AU - Roifman, Maian
AU - Cohn, Ronald
AU - Chitayat, David
AU - Millard, Tom H.
AU - Katsanis, Nicholas
AU - Brunner, Han G.
AU - Banka, Siddharth
AU - Deciphering Dev Disorders Study
PY - 2017/9/7
Y1 - 2017/9/7
N2 - RAC1 is a widely studied Rho GTPase, a class of molecules that modulate numerous cellular functions essential for normal development. RAC1 is highly conserved across species and is under strict mutational constraint. We report seven individuals with distinct de novo missense RAC1 mutations and varying degrees of developmental delay, brain malformations, and additional phenotypes. Four individuals, each harboring one of c.53G>A (p.Cys18Tyr), c.116A>G (p.Asn39Ser), c.218C>T (p.Pro73Leu), and c.470G>A (p.Cys157Tyr) variants, were microcephalic, with head circumferences between -2.5 to -5 SD. In contrast, two individuals with c.151G>A (p.Val51Met) and c.151G>C (p.Val51Leu) alleles were macrocephalic with head circumferences of +4.16 and +4.5 SD. One individual harboring a c.190T>G (p.Tyr64Asp) allele had head circumference in the normal range. Collectively, we observed an extraordinary spread of similar to 10 SD of head circumferences orchestrated by distinct mutations in the same gene. In silico modeling, mouse fibroblasts spreading assays, and in vivo overexpression assays using zebrafish as a surrogate model demonstrated that the p.Cys18Tyr and p.Asn39Ser RAC1 variants function as dominant-negative alleles and result in microcephaly, reduced neuronal proliferation, and cerebellar abnormalities in vivo. Conversely, the p.Tyr64Asp substitution is constitutively active. The remaining mutations are probably weakly dominant negative or their effects are context dependent. These findings highlight the importance of RAC1 in neuronal development. Along with TRIO and HACE1, a sub-category of rare developmental disorders is emerging with RAC1 as the central player. We show that ultra-rare disorders caused by private, non-recurrent missense mutations that result in varying phenotypes are challenging to dissect, but can be delineated through focused international collaboration.
AB - RAC1 is a widely studied Rho GTPase, a class of molecules that modulate numerous cellular functions essential for normal development. RAC1 is highly conserved across species and is under strict mutational constraint. We report seven individuals with distinct de novo missense RAC1 mutations and varying degrees of developmental delay, brain malformations, and additional phenotypes. Four individuals, each harboring one of c.53G>A (p.Cys18Tyr), c.116A>G (p.Asn39Ser), c.218C>T (p.Pro73Leu), and c.470G>A (p.Cys157Tyr) variants, were microcephalic, with head circumferences between -2.5 to -5 SD. In contrast, two individuals with c.151G>A (p.Val51Met) and c.151G>C (p.Val51Leu) alleles were macrocephalic with head circumferences of +4.16 and +4.5 SD. One individual harboring a c.190T>G (p.Tyr64Asp) allele had head circumference in the normal range. Collectively, we observed an extraordinary spread of similar to 10 SD of head circumferences orchestrated by distinct mutations in the same gene. In silico modeling, mouse fibroblasts spreading assays, and in vivo overexpression assays using zebrafish as a surrogate model demonstrated that the p.Cys18Tyr and p.Asn39Ser RAC1 variants function as dominant-negative alleles and result in microcephaly, reduced neuronal proliferation, and cerebellar abnormalities in vivo. Conversely, the p.Tyr64Asp substitution is constitutively active. The remaining mutations are probably weakly dominant negative or their effects are context dependent. These findings highlight the importance of RAC1 in neuronal development. Along with TRIO and HACE1, a sub-category of rare developmental disorders is emerging with RAC1 as the central player. We show that ultra-rare disorders caused by private, non-recurrent missense mutations that result in varying phenotypes are challenging to dissect, but can be delineated through focused international collaboration.
KW - RHO GTPASES
KW - INTELLECTUAL DISABILITY
KW - EXPRESSION
KW - VARIANTS
KW - SURVIVAL
KW - SPECTRUM
KW - SYSTEM
KW - FAMILY
KW - GROWTH
KW - CDC42
U2 - 10.1016/j.ajhg.2017.08.007
DO - 10.1016/j.ajhg.2017.08.007
M3 - Article
C2 - 28886345
SN - 0002-9297
VL - 101
SP - 466
EP - 477
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 3
ER -