DM transcriptomic profiles identified differentially express

DM2 transcriptomic profiles identified 14 differentially expressed genes, which possibly contribute to the onset of myalgias in DM2 patients. One of the identified differentially expressed genes encodes monoamine oxidase A (MAOA). Polymorphisms in the MAOA gene have been proposed to segregate with low and high pain responders, however, the genetic evidence is weak (Di Lorenzo et al., 2014; Kim et al., 2006). MAOA has been proposed as a therapeutic target in fibromyalgia and treatment with a specific MAOA inhibitor, moclobemide, was administered to female patients with fibromyalgia in an earlier study (Hannonen et al., 1998). Moclobemide significantly decreased pain in fibromyalgia patients at the end of a 12weeks intervention period by 1.2 points on the VAS (5.7 to 4.5) compared to placebo group. Variations in MAOA have been associated with different perceptions of pain and pain-related evoked potentials (Di Lorenzo et al., 2014; Treister et al., 2011). Two recent studies also quantified MAOA gene perk inhibitor in human muscle biopsies and have associated high expression with insulin resistance (Elgzyri et al., 2012; Mason et al., 2011). In the context of insulin resistance, common in DM2, one of the up-regulated genes in myalgic patients was growth factor receptor-bound protein 14 (GRB14) which is a known negative regulator of insulin receptor signalling (Depetris et al., 2005). Another interesting finding was elevated expression of creatine transporter SLC16A12 in myalgic DM2 which might be related to increased muscle wasting and inflammatory pain (Abplanalp et al., 2013). Interestingly, there is already a small molecule inhibitor identified for the 6-phosphofructo-2-kinase (PFKFB2) enzyme (Telang et al., 2012) the expression of which was up-regulated in the muscle of DM2 patient with myalgia. Thus, our approach may open new avenues to explore the link between novel genes associated with pain and therapeutic interventions at least in animal models. High variability in pain character and pathophysiology in patients with chronic pain has made it difficult to identify tailored pain medication that show selective efficacy in sub-populations of patients. However, emerging genomic strategies might facilitate the development of new and more effective pain therapeutics (Dib-Hajj and Waxman, 2014). The molecular signature of myalgia shown in this study may also help to identify pathways that are associated with pain in other conditions affecting skeletal muscle. Identifying the molecular source of pain pathophysiology should greatly facilitate focussing effective treatments, although major hurdles remain.
Contributions
Declaration of interests
Funding This study was funded by the German Research Society (DFG, GK1631), KAP programme of Charité Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine.
Introduction Neurofibromatosis type 1 (NF1) is a multisystem autosomal dominantly inherited tumour predisposition neurocutaneous syndrome characterised by pigmentary skin changes and benign nerve sheath tumors (neurofibromas) (Anderson & Gutmann, 2015; Huson et al., 1988). NF1 affects around 1 in 1/1900–2500 live births (Huson et al., 1989; Evans et al., 2010; Uusitalo et al., 2015) and significantly reduces life expectancy primarily due to the development of Malignant Peripheral Nerve Sheath Tumors (MPNST) in around 10% of affected people, but also gliomas and other malignancies including breast cancer (Evans et al., 2011). The National Institutes of Health (NIH) defined diagnostic criteria in 1987 (National Institutes of Health Consensus Development Conference, 1987) and these have largely remained unchanged also including bone dysplasia and Lisch nodules as criteria (Table 1) (Anderson & Gutmann, 2015; Gutmann et al., 1997). For such a large gene containing 58 coding exons (Shen et al., 1996) little is still known about domains outside the GTPase-activating protein-related domain (GRD) domain which is thought to be the main region associated with tumour suppression through down-regulation of the oncogene ras (Anderson & Gutmann, 2015; Ferner, 2007). There are substantial risks of neurological deficits including cognitive impairment, epilepsy, spinal cord compression, cerebrovascular disease, and multiple sclerosis (Ferner, 2007).