Clinical and genetic analysis of children with a dual diagnosis of Tourette syndrome and autism spectrum disorder.

Gilles de la Tourette Syndrome (TS) is a neurodevelopmental disorder that causes children to make repeated, brief involuntary movements or sounds. TS can be co-morbid with other neurodevelopmental disorders, including autism spectrum disorder (ASD). Clusters of biologically related genes have been associated with neurodevelopmental disorders, suggesting shared pathologies. However, the genetic contribution to TS remains poorly defined. We asked whether children with both TS and ASD differed clinically from children with ASD alone, and identified potentially deleterious genetic events in children with TS and ASD. We compared clinical data from 119 children with ASD and TS to 2603 children with ASD, all from the Simons Simplex Collection. We performed gene set enrichment analysis on de novo genetic events in children with both TS and ASD to identify candidate genes and pathways, and compared these genes and pathways with those previously identified in TS. Children with TS and ASD were diagnosed at an older age, had higher IQ scores, and had more restricted and repetitive behavior than children with ASD but not TS. Gene Ontology analysis revealed that proteins important for specific biological pathways, including regulation of calcium ion-dependent exocytosis, basement membrane organization, and visual behavior and learning, and specific cellular pathways, including basal lamina and ciliary transition zone, are enriched among genes with de novo mutations in children with TS and ASD. Clinical and genetic analysis of cohorts of affected children can help to determine the underlying pathophysiology of TS and other neurodevelopmental disorders.

The Prader-Willi syndrome proteins MAGEL2 and necdin regulate leptin receptor cell surface abundance through ubiquitination pathways.

In Prader-Willi syndrome (PWS), obesity is caused by the disruption of appetite-controlling pathways in the brain. Two PWS candidate genes encode MAGEL2 and necdin, related melanoma antigen proteins that assemble into ubiquitination complexes. Mice lacking Magel2 are obese and lack leptin sensitivity in hypothalamic pro-opiomelanocortin neurons, suggesting dysregulation of leptin receptor (LepR) activity. Hypothalamus from Magel2-null mice had less LepR and altered levels of ubiquitin pathway proteins that regulate LepR processing (Rnf41, Usp8, and Stam1). MAGEL2 increased the cell surface abundance of LepR and decreased their degradation. LepR interacts with necdin, which interacts with MAGEL2, which complexes with RNF41 and USP8. Mutations in the MAGE homology domain of MAGEL2 suppress RNF41 stabilization and prevent the MAGEL2-mediated increase of cell surface LepR. Thus, MAGEL2 and necdin together control LepR sorting and degradation through a dynamic ubiquitin-dependent pathway. Loss of MAGEL2 and necdin may uncouple LepR from ubiquitination pathways, providing a cellular mechanism for obesity in PWS.