Timing and localization of myasthenia gravis-related gene expression

Abstract

Myasthenia gravis (MG) is an acquired autoimmune disorder caused by autoantibodies binding acetylcholine receptors (AChR), muscle-specific kinase (MuSK), agrin or low-density lipoprotein receptor-related protein 4 (Lrp4). These autoantibodies inhibit neuromuscular transmission by blocking the function of these proteins and thereby cause fluctuating skeletal muscle weakness. Several reports suggest that these autoantibodies might also affect the central nervous system (CNS) in MG patients. A comprehensive overview of the timing and localization of the expression of MG-related antigens in other organs is currently lacking. To investigate the spatio-temporal expression of MG-related genes outside skeletal muscle, we used in silico tools to assess public expression databases. Acetylcholine esterase, nicotinic AChR α1 subunit, agrin, collagen Q, downstream of kinase-7, Lrp4, MuSK and rapsyn were included as MG-related genes because of their well-known involvement in either congenital or autoimmune MG. We investigated expression of MG-related genes in (1) all human tissues using GTEx data, (2) specific brain regions, (3) neurodevelopmental stages, and (4) cell types using datasets from the Allen Institute for Brain Sciences. MG-related genes show heterogenous spatio-temporal expression patterns in the human body as well as in the CNS. For each of these genes, several (new) tissues, brain areas and cortical cell types with (relatively) high expression were identified suggesting a potential role for these genes outside skeletal muscle. The possible presence of MG-related antigens outside skeletal muscle suggests that autoimmune MG, congenital MG or treatments targeting the same proteins may affect MG-related protein function in other organs.

Keywords: Dok7; Lrp4; MuSK; brain; myasthenia gravis; neuromuscular junction.