Biallelic ELMO3 mutations and loss of function for DOCK-mediated RAC1 activation result in intellectual disability
| Autor: | Daniel Martín Fernández-Mayoralas, Alberto Fernández-Jaén, Beatriz Calleja-Pérez, Marie-Anne Goyette, Sara Álvarez, Ana Laura Fernández-Perrone, Mónica Martínez-García, Jean-François Côté, Ana Jiménez de Domingo, Viviane Tran, Pilar Tirado |
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| Rok vydání: | 2021 |
| Předmět: |
0303 health sciences
Mutación Deficiencia mental Motility RAC1 Cell migration Cell Biology Genética humana Biology medicine.disease Biochemistry Cell biology 03 medical and health sciences 0302 clinical medicine Autism spectrum disorder 030220 oncology & carcinogenesis DOCK Intellectual disability medicine Trastorno del espectro autista Guanine nucleotide exchange factor Loss function 030304 developmental biology |
| Zdroj: | ABACUS. Repositorio de Producción Científica Universidad Europea (UEM) |
| ISSN: | 2154-1256 2154-1248 |
| Popis: | 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. CIHR grant (PJT-153065) No data JCR 2020 1.302 SJR (2021) Q1, 78/439 Biochemistry No data IDR 2020 UEM |
| Databáze: | OpenAIRE |
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