Children with the rare genetic disorder Prader-Willi syndrome have a high rate of autism spectrum disorders, with features including restricted and repetitive, compulsive and self-injurious behaviors. They also typically present with neonatal feeding difficulties, developmental delay, endocrine dysfunction and obesity. Prader-Willi syndrome is usually caused by the inactivation of a group of genes on chromosome 15. Spontaneous, or de novo, inactivating mutations in one of those genes, MAGEL2, have been identified in four children who have autism and other features of Prader-Willi syndrome. Loss of MAGEL2 function is likely to be responsible for autism predisposition in children with Prader-Willi syndrome.
Rachel Wevrick and her team at the University of Alberta in Edmonton, Canada, have been investigating MAGEL2 in cellular and mouse models. MAGEL2 and other members of the MAGE (melanoma antigen) protein family are important for the function of a set of proteins called E3 ubiquitin ligases. E3 ligases facilitate post-translational protein ubiquitylation, a process that targets proteins for sorting to compartments within the cell, recycling to the cell membrane or for degradation when proteins are damaged or unneeded. Mutations in various ubiquitylation components have been identified in people with syndromic autism spectrum disorders, suggesting that appropriate ubiquitylation is important for neural development and connectivity.
Wevrick and her team aim to investigate the interactions between MAGEL2 and E3 ubiquitin ligases that are involved in neurodevelopmental processes and disorders. They hope to explore interactions between MAGEL2 and specific E3 ubiquitin ligases implicated in neurodevelopmental disorders, and to identify new interactions with ligases expressed in the brain. They aim to determine whether E3 ligases are dysregulated in mice lacking MAGEL2, and how missense variants in MAGEL2 or the genes encoding candidate E3 ligases could contribute to autism.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
