Multisystem proteinopathy: Where myopathy and motor neuron disease converge

Manisha K Korb; Virginia E Kimonis; Tahseen Mozaffar

doi:10.1002/mus.27097

Multisystem proteinopathy: Where myopathy and motor neuron disease converge

Muscle Nerve. 2021 Apr;63(4):442-454. doi: 10.1002/mus.27097. Epub 2020 Nov 3.

Authors

Manisha K Korb¹, Virginia E Kimonis², Tahseen Mozaffar^{1

3

4}

Affiliations

¹ Departments of Neurology, University of California Irvine, Orange, California, USA.
² Departments of Pediatrics, University of California Irvine, Orange, California, USA.
³ Departments of Orthopedic Surgery, University of California Irvine, Orange, California, USA.
⁴ Departments of Pathology & Laboratory Medicine, University of California Irvine, Orange, California, USA.

PMID: 33145792
DOI: 10.1002/mus.27097

Abstract

Multisystem proteinopathy (MSP) is a pleiotropic group of inherited disorders that cause neurodegeneration, myopathy, and bone disease, and share common pathophysiology. Originally referred to as inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD), attributed to mutations in the gene encoding valosin-containing protein (VCP), it has more recently been discovered that there are several other genes responsible for similar clinical and pathological phenotypes with muscle, brain, nerve, and bone involvement, in various combinations. These include heterogeneous nuclear ribonucleoprotein A2B1 and A1 (hnRNPA2B1, hnRNPA1), sequestosome 1 (SQSTM1), matrin 3 (MATR3), T-cell restricted intracellular antigen 1 (TIA1), and optineurin (OPTN), all of which share disruption of RNA stress granule function and autophagic degradation. This review will discuss each of the genes implicated in MSP, exploring the molecular pathogenesis, clinical features, current standards of care, and future directions for this diverse yet mechanistically linked spectrum of disorders.

Keywords: Paget disease of bone; VCP; amyotrophic lateral sclerosis; inclusion body myopathy; multiple system proteinopathy.

Publication types

Review

MeSH terms

Cell Cycle Proteins / genetics*
Cell Cycle Proteins / metabolism
Humans
Motor Neuron Disease / genetics
Motor Neuron Disease / metabolism
Motor Neuron Disease / pathology*
Mutation / genetics
Nuclear Matrix-Associated Proteins / genetics
Nuclear Matrix-Associated Proteins / metabolism
RNA-Binding Proteins / genetics*
RNA-Binding Proteins / metabolism
Valosin Containing Protein / genetics
Valosin Containing Protein / metabolism*

Substances

Cell Cycle Proteins
Nuclear Matrix-Associated Proteins
RNA-Binding Proteins
Valosin Containing Protein