Isolated inclusion body myopathy caused by a multisystem proteinopathy–linked hnRNPA1 mutation

摘要

Objective: To identify the genetic cause of isolated inclusion body myopathy (IBM) with autosomal dominant inheritance in 2 families. Methods: Genetic investigations were performed using whole-exome and Sanger sequencing of the heterogeneous nuclear ribonucleoprotein A1 gene ( hnRNPA1 ). The clinical and pathologic features of patients in the 2 families were evaluated with neurologic examinations, muscle imaging, and muscle biopsy. Results: We identified a missense p.D314N mutation in hnRNPA1 , which is also known to cause familial amyotrophic lateral sclerosis, in 2 families with IBM. The affected individuals developed muscle weakness in their 40s, which slowly progressed toward a limb-girdle pattern. Further evaluation of the affected individuals revealed no apparent motor neuron dysfunction, cognitive impairment, or bone abnormality. The muscle pathology was compatible with IBM, lacking apparent neurogenic change and inflammation. Multiple immunohistochemical analyses revealed the cytoplasmic aggregation of hnRNPA1 in close association with autophagosomes and myonuclei. Furthermore, the aberrant accumulation was characterized by coaggregation with ubiquitin, sequestome-1/p62, valosin-containing protein/p97, and a variety of RNA-binding proteins (RBPs). Conclusions: The present study expands the clinical phenotype of hnRNPA1 -linked multisystem proteinopathy. Mutations in hnRNPA1 , and possibly hnRNPA2B1 , will be responsible for isolated IBM with a pure muscular phenotype. Although the mechanisms underlying the selective skeletal muscle involvement remain to be elucidated, the immunohistochemical results suggest a broad sequestration of RBPs by the mutated hnRNPA1 . Multisystem proteinopathy (MSP) is an inherited pleiotropic degenerative disorder that can affect muscle, bone, and/or the nervous system. MSP is genetically heterogeneous and has been associated with mutations in VCP , 1 hnRNPA1 , 2 hnRNPA2B1 , 2 SQSTM1/p62 , 3 and MATR3 genes. 4 , 5 Heterogeneous nuclear ribonucleoproteins (hnRNPs) are ubiquitously expressed RNA-binding proteins (RBPs) that are involved in messenger RNA metabolism and transport. In 2013, novel missense mutations in the prion-like domain (PrLD) of hnRNPA1 and hnRNPA2B1 genes were identified in patients with MSP/amyotrophic lateral sclerosis (ALS), 2 which were later designated as MSP3 and MSP2, respectively. 6 Subsequent to the discovery of hnRNPA1 and hnRNPA2B1 mutations, screening of these genes resulted in no additional mutation in Dutch, 7 French, 8 and Italian 9 patients with ALS, frontotemporal dementia, inclusion body myopathy (IBM), or MSP, which suggests that MSP3 and MSP2 are rarer than expected. We identified an MSP3-linked hnRNPA1 mutation by exome sequencing and segregating study in 2 unrelated Japanese families that presented with dominantly inherited IBM without bone or CNS involvement. The pure muscular phenotype is distinct from that of previously described MSP3 cases and is believed to be a novel MSP3 phenotype. In this study, we report clinical, genetic, and histopathologic features of the 2 pedigrees.