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SUMMARY:RAC1 mutations in human neurodevelopmental disorders - Dr Siddhart
 h Banka &amp\; Dr Thomas Millard\; University of Manchester
DTSTART:20200720T110000Z
DTEND:20200720T120000Z
UID:TALK149851@talks.cam.ac.uk
CONTACT:Bobbie Claxton
DESCRIPTION:RAC1 is a highly conserved Rho GTPase under strict mutational 
 constraint. We describe patients with novel human disorder caused by germl
 ine de novo missense RAC1 mutations resulting in varying degrees of develo
 pmental delay\, brain malformations\, and additional phenotypes (1). Colle
 ctively\, we observed an extraordinary spread of ∼10 SD of head circumfe
 rences orchestrated by distinct mutations in the same gene. In silico mode
 lling\, mouse fibroblasts spreading assays\, and in vivo over-expression a
 ssays using zebrafish as a surrogate model demonstrated that the some RAC1
  variants function as dominant-negative alleles and result in microcephaly
 \, reduced neuronal proliferation\, and cerebellar abnormalities in vivo. 
 Conversely\, some variants are constitutively active or their effects are 
 context dependent. Currently we are working to expand the known spectrum o
 f germline RAC1 mutations and improve the understanding of the mechanism o
 f the disease. More recently\, other Rho GTPases and their regulators have
  also been implicated in human neurodevelopmental disorders. Overall\, the
 se findings highlight the importance of Rho GTPases in normal human neurod
 evelopment and disease.  \n1. Reijnders et al  Am J Hum Genet 2017 101 (3)
 . \n\n\nJoin Zoom seminar:\nhttps://zoom.us/j/98168116369?pwd=Vmc5MnFyYTR4
 SEdyNjQxMDdOK1E4UT09\n\nMeeting ID:        981 6811 6369\nPassword:       
     803531
LOCATION:Zoom Seminar
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