Abstract
BackgroundWhile extraocular muscles are affected early in myasthenia gravis (MG), but respond to treatment, we observe a high incidence of treatment-resistant ophthalmoplegia (OP-MG) among MG subjects with African genetic ancestry. Previously, using whole exome sequencing, we reported potentially functional variants which associated with OP-MG. The aim of this study was to profile the expression of genes harbouring the OP-MG associated variants using patient-derived subphenotype-specific ‘myocyte’ cultures.MethodsFrom well-characterised MG patients we developed the ‘myocyte’ culture models by transdifferentiating dermal fibroblasts using an adenovirus expressing MyoD. These myocyte cultures were treated with homologous acetylcholine receptor antibody-positive myasthenic sera to induce muscle transcripts in response to an MG stimulus. Gene expression in myocytes derived from OP-MG (n = 10) and control MG subjects (MG without ophthalmoplegia; n = 6) was quantified using a custom qPCR array profiling 93 potentially relevant genes which included the putative OP-MG susceptibility genes and other previously reported genes of interest in MG and experimental autoimmune myasthenia gravis (EAMG).ResultsOP-MG myocytes compared to control MG myocytes showed altered expression of four OP-MG susceptibility genes (PPP6R2, CANX, FAM136A and FAM69A) as well as several MG and EAMG genes (p < 0.05). A correlation matrix of gene pair expression levels revealed that 15% of gene pairs were strongly correlated in OP-MG samples (r > 0.78, p < 0.01), but not in control MG samples. OP-MG susceptibility genes and MG-associated genes accounted for the top three significantly correlated gene pairs (r ≥ 0.98, p < 1 × 10− 6) reflecting crosstalk between OP-MG and myasthenia pathways, which was not evident in control MG cells. The genes with altered expression dynamics between the two subphenotypes included those with a known role in gangliosphingolipid biosynthesis, mitochondrial metabolism and the IGF1-signalling pathway.ConclusionUsing a surrogate cell culture model our findings suggest that muscle gene expression and co-expression differ between OP-MG and control MG individuals. These findings implicate pathways not previously considered in extraocular muscle involvement in myasthenia gravis and will inform future studies.
Highlights
While extraocular muscles are affected early in myasthenia gravis (MG), but respond to treatment, we observe a high incidence of treatment-resistant ophthalmoplegia (OP-MG) among MG subjects with African genetic ancestry
Though the incidence of MG in sub-Saharan Africa is comparable to world figures [4], we observe a high frequency of treatment-resistant ophthalmoplegia in this region characterized by severe, persistent eye muscle weakness, which we refer to as OP-MG [5]
There were no differences in the expression of these three muscle specific genes between control MG and OP-MG in both the early and late models indicating a similar degree of myogenic differentiation in both subphenotypes) (Fig. 3b)
Summary
While extraocular muscles are affected early in myasthenia gravis (MG), but respond to treatment, we observe a high incidence of treatment-resistant ophthalmoplegia (OP-MG) among MG subjects with African genetic ancestry. Myasthenia gravis (MG) is a rare antibody-mediated neuromuscular disease in which predominantly acetylcholine receptor (AChR) antibodies target the muscle endplate resulting in fatigable weakness of skeletal muscles. Though the incidence of MG in sub-Saharan Africa is comparable to world figures [4], we observe a high frequency of treatment-resistant ophthalmoplegia in this region characterized by severe, persistent eye muscle weakness, which we refer to as OP-MG [5]. OP-MG most commonly affects subjects with juvenile onset, but otherwise characteristic AChR antibody-positive MG (i.e. generalized muscle weakness which responds to treatment) [6].
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