RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes

Margot R. F. Reijnders, Nurhuda M. Ansor, Maria Kousi, Wyatt W. Yue, Perciliz L. Tan, Katie Clarkson, Jill Clayton-Smith, Ken Corning, Julie R. Jones, Wayne W. K. Lam, Grazia M. S. Mancini, Carlo Marcelis, Shehla Mohammed, Rolph Pfundt, Maian Roifman, Ronald Cohn, David Chitayat, Tom H. Millard, Nicholas Katsanis, Han G. Brunner*Siddharth Banka*, Deciphering Dev Disorders Study

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

75 Citations (Web of Science)

Abstract

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.

Original languageEnglish
Pages (from-to)466-477
Number of pages12
JournalAmerican Journal of Human Genetics
Volume101
Issue number3
DOIs
Publication statusPublished - 7 Sep 2017

Keywords

  • RHO GTPASES
  • INTELLECTUAL DISABILITY
  • EXPRESSION
  • VARIANTS
  • SURVIVAL
  • SPECTRUM
  • SYSTEM
  • FAMILY
  • GROWTH
  • CDC42

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