PT  - JOURNAL ARTICLE
AU  - Izumi, Rumiko
AU  - Warita, Hitoshi
AU  - Niihori, Tetsuya
AU  - Takahashi, Toshiaki
AU  - Tateyama, Maki
AU  - Suzuki, Naoki
AU  - Nishiyama, Ayumi
AU  - Shirota, Matsuyuki
AU  - Funayama, Ryo
AU  - Nakayama, Keiko
AU  - Mitsuhashi, Satomi
AU  - Nishino, Ichizo
AU  - Aoki, Yoko
AU  - Aoki, Masashi
TI  - Isolated inclusion body myopathy caused by a multisystem proteinopathy–linked <em>hnRNPA1</em> mutation
AID  - 10.1212/NXG.0000000000000023
DP  - 2015 Oct 01
TA  - Neurology Genetics
PG  - e23
VI  - 1
IP  - 3
4099  - http://ng.neurology.org/content/1/3/e23.short
4100  - http://ng.neurology.org/content/1/3/e23.full
SO  - Neurol Genet2015 Oct 01; 1
AB  - 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.ALS=amyotrophic lateral sclerosis; CK=creatine kinase; FUS/TLS=fused in sarcoma/translated in liposarcoma; hnRNP=heterogeneous nuclear ribonucleoprotein; IBM=inclusion body myopathy; MSP=multisystem proteinopathy; PDB=Paget disease of bone; PrLD=prion-like domain; RBP=RNA-binding protein; SNV=single nucleotide variant; SQSTM1/p62=sequestome-1/p62; TDP-43=transactive response DNA binding protein 43 kDa; Ub=ubiquitin; VCP=valosin-containing protein