Consistently, it was also reported that patients harboring the DOK7 mutations have abnormally small, simplified NMJs that show normal AChR and AChE function (20, 28). Taken together, these findings indicate that biallelic DOK7 mutations underlie an NMJ synaptopathy that causes a new disease entity, DOK7 CMS. DOK7 CMS patients have some distinct clinical features that provide clues for diagnosis (20–22). As mentioned above, proximal muscles are usually more affected than distal ones. As

with other CMS, ptosis is often present from an early age; Inhibitors,research,lifescience,medical however, eye movements are rarely involved. In selleck chemicals llc general, patients with DOK7 CMS do not show long-term benefit from anticholinesterase medication but frequently responded to ephedrine. Inhibitors,research,lifescience,medical Interestingly, this phenotype can be distinguished from limb girdle myasthenia associated with tubular aggregates

in the skeletal muscle, where DOK7 mutations were not detected and patients do respond to anticholinesterase medication. Although these clinical features help diagnosis and appropriate managements, molecular mechanisms underlying these characteristic phenotypes of DOK7 CMS Inhibitors,research,lifescience,medical are as yet unclear. Are additional components of the Dok-7/MuSK pathway involved in CMS? DOK7 CMS has been established as a newly recognized disorder. Although CMS-associated genetic mutations have been identified in 11 genes, in many patients causative mutations cannot be found. There is an aforementioned subgroup of CMS patients with a limb girdle pattern of muscle weakness, Inhibitors,research,lifescience,medical who have tubular aggregates when muscle biopsies are analyzed in whom genetic mutations have not yet been identified (28). It is likely that additional elements will be identified that play important

roles in AChR assembly, and NMJ formation and maintenance. For example, Low-density lipoprotein receptor-related Inhibitors,research,lifescience,medical protein 4 (Lrp4) has recently been identified as an essential Ganetespib clinical trial molecule for the postsynaptic specialization of NMJ (30). Defects found in the skeletal muscle of mice lacking Lrp4 are indistinguishable from those in MuSK- or Dok-7-deficient mice; namely, failure to cluster AChRs and exuberant growth of motor nerve axons in embryos. However, how this receptor-like transmembrane protein plays a role in Dok-7 and MuSK-dependent AChR clustering is unknown. A comprehensive understanding of the molecular mechanisms of NMJ formation and maintenance, in which the Dok-7/MuSK pathway is central, may contribute to identification of other causative mutations of CMS and to the discovery of potential therapeutic targets.