TY - JOUR A1 - Tran, Viviane AU - Goyette, Marie-Anne AU - Martínez García, Mónica AU - Jiménez de Domingo, Ana AU - Fernández Mayoralas, Daniel Martín AU - Fernández Perrone, Ana Laura AU - Tirado, Pilar AU - Calleja Pérez, Beatriz AU - Álvarez de Andrés, Sara AU - Côté, Jean-François AU - Fernández Jaén, Alberto T1 - Biallelic ELMO3 mutations and loss of function for DOCK-mediated RAC1 activation result in intellectual disability Y1 - 2022 SN - 2154-1248 UR - http://hdl.handle.net/11268/11364 AB - The engulfment and cell motility 3 (ELMO3) protein belongs to the ELMO-family of proteins. ELMO proteins form a tight complex with the DOCK1-5 guanine nucleotide exchange factors that regulate RAC1 spatiotemporal activation and signalling. DOCK proteins and RAC1 are known to have fundamental roles in central nervous system development. Here, we searched for homozygous or compound heterozygous mutations in the ELMO3 gene in 390 whole exomes sequenced in trio in individuals with neurodevelopmental disorders compatible with a genetic origin. We found a compound heterozygous mutation in ELMO3 (c.1153A>T, p.Ser385Cys and c.1009 G > A, p.Val337Ile) in a 5 year old male child with autism spectrum disorder (ASD) and developmental delay. These mutations did not interfere with the formation of an ELMO3/DOCK1 complex, but markedly impaired the ability of the complex to promote RAC1-GTP-loading. Consequently, cells expressing DOCK1 and either of the ELMO3 mutants displayed impaired migration and invasion. Collectively, our results suggest that biallelic loss-of-function mutations in ELMO3 may cause a developmental delay and provide new insight into the role of ELMO3 in neurodevelopmental as well as the pathological consequences of ELMO3 mutations. KW - Trastorno del espectro autista KW - Deficiencia mental KW - Genética humana KW - Mutación LA - eng ER -