Proteomic profiling of sporadic late‐onset nemaline myopathy

Abstract

Objective To define the proteomic profile of sporadic late‐onset nemaline myopathy (SLONM) and explore its pathogenesis. Methods We performed mass spectrometry on laser‐dissected frozen muscle samples from five patients with SLONM, three of whom with an associated monoclonal protein (MP), and four controls, to determine the proteomic profile of SLONM. Furthermore, we assessed the role of the MP by evaluating the expression of the immunoglobulin light chain variable regions (IGVL). Results There were 294 differentially expressed proteins: 272 upregulated and 22 downregulated. Among the top 100 upregulated proteins, the most common categories were: nuclear or nucleic acid metabolism (24%), extracellular matrix and basal lamina (17%), immune response (13%), and actin dynamics (8%). Downregulated proteins consisted mostly of contractile proteins. Among upregulated proteins, there were 65 with a role related to the immune system, including eight proteins involved in major histocompatibility complex 1 (MHC1) and antigen processing, 15 in MHCII complex and phagocytosis, and 23 in B and/or T‐cell function. Among nine upregulated immunoglobulin proteins, there were two IGVL genes. However, these were also detected in SLONM cases without an MP, with no evidence of clonally dominant immunoglobulin deposition. In muscle sections from SLONM patients, nemaline rods tended to accumulate in atrophic fibers with marked rarefaction of the myofibrils. Increased MHC1 reactivity was present in fibers containing nemaline rods as well as adjacent nonatrophic fibers. Conclusion Our findings suggest that aberrant immune activation is present in SLONM, but do not support a direct causal relationship between the MP and SLONM.

Molecular signatures of inherited and acquired sporadic late onset nemaline myopathies

“…In addition to these, extracellular matrix and nuclear proteins were over-represented in nemaline rod areas in our samples. A similar finding was observed in a recent proteomic analysis comparing rod-containing fibers from 5 SLONM patients to healthy control tissue [ 42 ]. Presence of extracellular matrix proteins accompanying the accumulation of Z-disc-related proteins was also shown by proteomic studies within protein aggregates in myotilinopathy and filaminopathy, two myofibrillar myopathies [ 43 , 44 ].…”

“…Thus, it also provides further rationale for the use of plasma cell targeting chemotherapy for treatment of SLONM [ 55 ]. While all SLONM specimens showed MHC-I reactivity predominantly involving atrophic fibers, as previously reported [ 42 ], only 5 demonstrated diffuse kappa LC sarcoplasmic staining. Due to extreme heterogeneity of treatment (including intravenous immunoglobulins, methylprednisolone, methotrexate, mycophenolate mofetil, and autologous stem cell transplant) and variable length of follow-up, we were unable to assess whether patients with SLONM who had kappa LC-positive muscle fibers responded better to treatment.…”

Sporadic late onset nemaline myopathy with concurrent dermatological symptoms responding to immunosuppressive treatment

“…An immune-mediated etiology has been implicated in SLONM [2] [3] [4] [5] [9]. Inflammatory features such as CD68 positive macrophage infiltration, mild MHC expression have been reported without the presence of lymphocytes [2] [4].…”

“…Another study showed evidence for upregulation of immune-related proteins despite the lack of inflammation on muscle biopsy in SLONM [9], suggesting that immune-related processes are involved in all cases, but to various extent. MGUS could be a sign for a more aggressive immune response [9].…”