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

ABSTRACT: 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.

SUBMITTER: Izumi R

PROVIDER: S-EPMC4809462 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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

Izumi Rumiko R Warita Hitoshi H Niihori Tetsuya T Takahashi Toshiaki T Tateyama Maki M Suzuki Naoki N Nishiyama Ayumi A Shirota Matsuyuki M Funayama Ryo R Nakayama Keiko K Mitsuhashi Satomi S Nishino Ichizo I Aoki Yoko Y Aoki Masashi M

Neurology. Genetics 20150924 3

<h4>Objective</h4>To identify the genetic cause of isolated inclusion body myopathy (IBM) with autosomal dominant inheritance in 2 families.<h4>Methods</h4>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.<h4>Results</h4>We identified a missense p.D314N mutat ...[more]

PMID: 27066560

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Project description:The 2021 VCP Scientific Conference took place virtually from September 9-10, 2021. This conference, planned and organized by the nonprofit patient advocacy group Cure VCP Disease, Inc. (https://www.curevcp.org), was the first VCP focused meeting since the 215th ENMC International Workshop VCP-related multi-system proteinopathy in 2016 (Evangelista et al., 2016). Mutations in VCP cause a complex and heterogenous disease termed inclusion body myopathy (IBM) with Paget's disease of the bone (PDB) and frontotemporal dementia (FTD) (IBMPFD), or multisystem proteinopathy 1 (MSP-1) Kimonis (n.d.), Kovach et al. (2001), Kimonis et al. (2000). In addition, VCP mutations also cause other age-related neurodegenerative disorders including amyptrophic lateral sclerosis (ALS), Parkinsonism, Charcot-Marie type II-B, vacuolar tauopathy among others (Korb et al., 2022). The objectives of this conference were as follows: (1) to provide a forum that facilitates sharing of published and unpublished information on physiological roles of p97/VCP, and on how mutations of VCP lead to diseases; (2) to bolster understanding of mechanisms involved in p97/VCP-relevant diseases and to enable identification of therapeutics to treat these conditions; (3) to identify gaps and barriers of further discoveries and translational research in the p97/VCP field; (4) to set a concrete basic and translational research agenda for future studies including crucial discussions on biomarker discoveries and patient longitudinal studies to facilitate near-term clinical trials; (5) to accelerate cross-disciplinary research collaborations among p97/VCP researchers; (6) to enable attendees to learn about new tools and reagents with the potential to facilitate p97/VCP research; (7) to assist trainees in propelling their research and to foster mentorship from leaders in the field; and (8) to promote diversity and inclusion of under-represented minorities in p97/VCP research as diversity is critically important for strong scientific research. Given the range of topics, the VCP Scientific Conference brought together over one hundred and forty individuals representing a diverse group of research scientists, trainees, medical practitioners, industry representatives, and patient advocates. Twenty-five institutions with individuals from thirteen countries attended this virtual meeting. In this report, we summarize the major topics presented at this conference by a range of experts.

Dataset Information

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

Publications

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

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