Sex-Linked Neuroligins and Their Roles at Synapses
Roche, Katherine W
Autism spectrum disorder (ASD) is a neurodevelopmental disorder that results in social-communication impairments, restricted and repetitive behaviors, and is more prevalent in males. Although the underlying etiology of ASD is generally unknown, a cell adhesion molecule, Neuroligin 4X (NLGN4X) located on the X chromosome, has been specifically linked with this disorder. The male-specific NLGN4Y, the NLGN4X homolog, is thought to be functionally redundant, but this assumption has not been experimentally tested.In this dissertation, we report NLGN4X and NLGN4Y are functionally different. NLGN4Y does not effectively traffic to the surface or induce synapses. We show that a critical amino acid difference in the extracellular domain (ECD) between NLGN4X (P93) and NLGN4Y (S93) leads to this differential function. In addition, we show that NLGN4X is robustly phosphorylated by protein kinase A and protein kinase C, whereas NLGN4Y cannot. The differential phosphorylation is due to one amino acid difference in the intracellular domain (ICD) between NLGN4X (R710) and NLGN4Y (H710). Together, we demonstrate that NLGN4X and NLGN4Y do not share the same function.Interestingly, many ASD-associated variants have been identified in NLGN4X in the region surrounding P93, and there is a decrease in normal population variation in this region. In addition, we describe two new variants found in probands with ASD and intellectual disability (ID), NLGN4X R101Q and V109L. Intriguingly, several of the ASD-associated mutations in NLGN4X are found in males with mothers who are carriers. Furthermore, an ASD-associated mutation in the ICD of NLGN4X disrupt both PKC and PKA phosphorylation. Taken together, our results reveal that NLGN4Y cannot compensate for NLGN4X function due to a defect in trafficking to the cell surface and phosphorylation, revealing potential pathogenic mechanisms for male bias in NLGN4X-associated ASD cases.
Showing items related by title, author, creator and subject.
Reducing Maternal Mortality: Actual and Potential Roles for Faith-linked Institutions and Communities Unknown author (2011-11-10)This report reviews the work of faith-inspired leaders, communities, and organizations in worldwide efforts to reduce maternal mortality. Maternal mortality rates represent one of the most extreme cases of inequality in ...