A novel deletion in the C-terminal region of HSPB8 in a family with rimmed vacuolar myopathy

Inoue-Shibui, Aya; Niihori, Tetsuya; Kobayashi, Michio; Suzuki, Naoki; Izumi, Rumiko; Warita, Hitoshi; Hara, Kenju; Shirota, Matsuyuki; Funayama, Ryo; Nakayama, Keiko; Nishino, Ichizo; Akiyama, Masashi; Aoki, Yoko

doi:10.1038/s10038-021-00916-y

Cited by 7 publications

(9 citation statements)

References 16 publications

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“…Additionally, HSPB8 and TFG were associated with motor neuronopathy, sensory neuropathy, rimmed vacuoles on muscle biopsy, and could represent MSP genes. While description of TFG‐related muscle pathology is limited (rimmed vacuoles in 1 patient 17 and sarcoplasmic TDP43/p62‐positive inclusions in 2 patients 18 ), myopathological features of HSPB8 ‐related disorder are well documented 19–22 . TFG chaperones misfolded proteins into the ubiquitin‐proteasome system and its most common mutation (p.Pro285L) damages the protein quality control 23 ; HSPB8 is also a chaperone participating in maintaining integrity and dynamics of stress granules, 24 functions shared with other MSP causing proteins.…”

Section: Introductionmentioning

confidence: 99%

“…While description of TFG‐related muscle pathology is limited (rimmed vacuoles in 1 patient 17 and sarcoplasmic TDP43/p62‐positive inclusions in 2 patients 18 ), myopathological features of HSPB8 ‐related disorder are well documented. 19 , 20 , 21 , 22 TFG chaperones misfolded proteins into the ubiquitin‐proteasome system and its most common mutation (p.Pro285L) damages the protein quality control 23 ; HSPB8 is also a chaperone participating in maintaining integrity and dynamics of stress granules, 24 functions shared with other MSP causing proteins. Lastly, there are genetic disorders manifesting only with neurodegeneration, such as TARDPB ‐related ALS/FTD, also featuring TDP‐43 mislocalization and ubiquitinated inclusions, 25 but not classified as MSPs due to lack of other system (muscle and bone) involvement.…”

Section: Introductionmentioning

confidence: 99%

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Multisystem proteinopathies (MSPs) and MSP‐like disorders: Clinical‐pathological‐molecular spectrum

Chompoopong

Oskarsson

Madigan

et al. 2023

Ann Clin Transl Neurol

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Objectives: Mutations in VCP, HNRNPA2B1, HNRNPA1, and SQSTM1, encoding RNA-binding proteins or proteins in quality-control pathways, cause multisystem proteinopathies (MSP). They share pathological findings of protein aggregation and clinical combinations of inclusion body myopathy (IBM), neurodegeneration [motor neuron disorder (MND)/frontotemporal dementia (FTD)], and Paget disease of bone (PDB). Subsequently, additional genes were linked to similar but not full clinical-pathological spectrum (MSP-like disorders). We aimed to define the phenotypic-genotypic spectrum of MSP and MSP-like disorders at our institution, including long-term follow-up features. Methods: We searched the Mayo Clinic database (January 2010-June 2022) to identify patients with mutations in MSP and MSP-like disorders causative genes. Medical records were reviewed. Results: Thirty-one individuals (27 families) had pathogenic mutations in: VCP (n = 17), SQSTM1 + TIA1 (n = 5), TIA1 (n = 5), MATR3, HNRNPA1, HSPB8, and TFG (n = 1, each). Myopathy occurred in all but 2 VCP-MSP patients with disease onset at age 52 (median). Weakness pattern was limb-girdle in 12/15 VCP-MSP and HSPB8 patient, and distal-predominant in other MSP and MSP-like disorders. Twenty/24 muscle biopsies showed rimmed vacuolar myopathy. MND and FTD occurred in 5 (4 VCP, 1 TFG) and 4 (3 VCP, 1 SQSTM1 + TIA1) patients, respectively. PDB manifested in 4 VCP-MSP. Diastolic dysfunction occurred in 2 VCP-MSP. After 11.5 years (median) from symptom onset, 15 patients ambulated without gaitaids; loss of ambulation (n = 5) and death (n = 3) were recorded only in VCP-MSP. Interpretation: VCP-MSP was the most common disorder; rimmed vacuolar myopathy was the most frequent manifestation; distal-predominant weakness occurred frequently in non-VCP-MSP; and cardiac involvement was observed only in VCP-MSP.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Multisystem proteinopathies (MSPs) and MSP‐like disorders: Clinical‐pathological‐molecular spectrum

Chompoopong

Oskarsson

Madigan

et al. 2023

Ann Clin Transl Neurol

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“…HSPB8 is also involved in RNA metabolism: HSPB8 can bind the RNA helicase DDX20, which is a component of Survival Motor Neuron (SMN) and small nuclear ribonucleoproteins (snRNP) complexes, and HSPB8 K141 mutants show alteration of DDX20 binding (Sun et al, 2010). Moreover, a deregulation in the RNA binding protein (RBP) TDP-43 activity has been observed in dHMN and MFM patients carrying the K141E mutation; in particular, alteration of splicing of TDP-43 target genes and decreased mRNA levels of TDP-43 correlating to HSPB8 aggregation were observed in patients muscles (Cortese et al, 2018) Al-Tahan et al, 2019;Nicolau et al, 2020;Inoue-Shibui et al, 2021). Although these mutations are often causative of primary myopathies, neurogenic involvement can be observed (Ghaoui et al, 2016).…”

Section: Hspb8mentioning

confidence: 99%

“…Strikingly, all these frameshift mutations fall in the CTD of HSPB8 and cause the production of HSPB8 proteins with a variably modified CTD and a common extended C-terminal tail, resulting from the use of an alternative downstream stop codon. Evaluation of the extended C-terminal tail by in silico tools revealed a decreased solubility and an increased aggregation propensity of a tract corresponding to the ILV tripeptide, which resembles the I/V-X-I/V domain shared by several HSPBs, but not present in HSPB8 (Inoue-Shibui et al, 2021). Interestingly, previous biochemical studies investigating HSPBs interaction with BAG3 showed that the introduction of the CTD of HSPB1, which presents a I/V-X-I/ V motif, into HSPB8, decreased HSPB8 solubility, suggesting a deleterious effect of I/V-X-I/V motif-like sequence on HSPB8 dynamics (Fuchs et al, 2009).…”

Section: Hspb8mentioning

confidence: 99%

Insights on Human Small Heat Shock Proteins and Their Alterations in Diseases

Tedesco

Cristofani

Ferrari

et al. 2022

Front. Mol. Biosci.

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The family of the human small Heat Shock Proteins (HSPBs) consists of ten members of chaperones (HSPB1-HSPB10), characterized by a low molecular weight and capable of dimerization and oligomerization forming large homo- or hetero-complexes. All HSPBs possess a highly conserved centrally located α-crystallin domain and poorly conserved N- and C-terminal domains. The main feature of HSPBs is to exert cytoprotective functions by preserving proteostasis, assuring the structural maintenance of the cytoskeleton and acting in response to cellular stresses and apoptosis. HSPBs take part in cell homeostasis by acting as holdases, which is the ability to interact with a substrate preventing its aggregation. In addition, HSPBs cooperate in substrates refolding driven by other chaperones or, alternatively, promote substrate routing to degradation. Notably, while some HSPBs are ubiquitously expressed, others show peculiar tissue-specific expression. Cardiac muscle, skeletal muscle and neurons show high expression levels for a wide variety of HSPBs. Indeed, most of the mutations identified in HSPBs are associated to cardiomyopathies, myopathies, and motor neuropathies. Instead, mutations in HSPB4 and HSPB5, which are also expressed in lens, have been associated with cataract. Mutations of HSPBs family members encompass base substitutions, insertions, and deletions, resulting in single amino acid substitutions or in the generation of truncated or elongated proteins. This review will provide an updated overview of disease-related mutations in HSPBs focusing on the structural and biochemical effects of mutations and their functional consequences.

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“…Another transgenic mouse developed to overexpress an HSPB8 mutation related to CMT disease (see below) was indeed characterized by protein accumulation and marked alteration of the motor behaviour associated with the degeneration of peripheral nerves and muscle atrophy [ 245 ]. Thus, these HSPB8 mutations are responsible for a GOF of this chaperone, explaining their role in some MNDs or neuromuscular diseases, such as dHMNs, CMT2, and myopathies [ 168 , 245 , 246 , 247 , 248 , 249 , 250 , 251 , 252 , 253 , 254 , 255 , 256 , 257 , 258 , 259 , 260 , 261 , 262 , 263 , 264 ].…”

Section: The Family Of the Small Hsps (Hspbs) And Their Role In Prote...mentioning

confidence: 99%

The Role of Small Heat Shock Proteins in Protein Misfolding Associated Motoneuron Diseases

Tedesco

Ferrari

Cozzi

et al. 2022

IJMS

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Motoneuron diseases (MNDs) are neurodegenerative conditions associated with death of upper and/or lower motoneurons (MNs). Proteostasis alteration is a pathogenic mechanism involved in many MNDs and is due to the excessive presence of misfolded and aggregated proteins. Protein misfolding may be the product of gene mutations, or due to defects in the translation process, or to stress agents; all these conditions may alter the native conformation of proteins making them prone to aggregate. Alternatively, mutations in members of the protein quality control (PQC) system may determine a loss of function of the proteostasis network. This causes an impairment in the capability to handle and remove aberrant or damaged proteins. The PQC system consists of the degradative pathways, which are the autophagy and the proteasome, and a network of chaperones and co-chaperones. Among these components, Heat Shock Protein 70 represents the main factor in substrate triage to folding, refolding, or degradation, and it is assisted in this task by a subclass of the chaperone network, the small heat shock protein (sHSPs/HSPBs) family. HSPBs take part in proteostasis by bridging misfolded and aggregated proteins to the HSP70 machinery and to the degradative pathways, facilitating refolding or clearance of the potentially toxic proteins. Because of its activity against proteostasis alteration, the chaperone system plays a relevant role in the protection against proteotoxicity in MNDs. Here, we discuss the role of HSPBs in MNDs and which HSPBs may represent a valid target for therapeutic purposes.

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A novel deletion in the C-terminal region of HSPB8 in a family with rimmed vacuolar myopathy

Cited by 7 publications

References 16 publications

Multisystem proteinopathies (MSPs) and MSP‐like disorders: Clinical‐pathological‐molecular spectrum

Multisystem proteinopathies (MSPs) and MSP‐like disorders: Clinical‐pathological‐molecular spectrum

Insights on Human Small Heat Shock Proteins and Their Alterations in Diseases

The Role of Small Heat Shock Proteins in Protein Misfolding Associated Motoneuron Diseases

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