Molecular genetics of J-domain protein-related chaperonopathies in skeletal muscle.

The J-domain proteins (JDPs), or HSP40s, are essential molecular co-chaperones that, in concert with HSP70, play a pivotal role in maintaining protein homeostasis, which is particularly critical in skeletal muscle. In recent years, pathogenic variants in several JDP-encoding genes have been identified as a cause of a growing group of inherited muscle diseases, termed JDP-related myopathies. This review provides a comprehensive overview of the current understanding of the molecular genetics, clinical phenotypes, muscle pathology, and pathomechanisms of myopathies caused by mutations in DNAJB6, DNAJB4, and DNAJB2.

Muscle Biopsy Findings in Valosin-Containing Protein Multisystem Proteinopathy.

Background And Objectives: Valosin Containing Protein-associated multisystem proteinopathy (VCP-MSP) is a progressive, autosomal dominant disorder caused by pathogenic variants in the VCP gene, resulting in a heterogeneous clinical presentation. Muscle biopsy findings are characteristic but not pathognomonic. This study aimed to comprehensively analyse VCP-related myopathology and explore correlations with clinical phenotypes, genetic variants, and disease progression.

Myofibrillar myopathy: towards a mechanism-based definition as a Z-disk-opathy.

Purpose Of Review: Myofibrillar myopathies (MFMs) are traditionally defined by histopathology, but recent genetic discoveries have broadened the spectrum of causative genes beyond Z-disk components. This review aims to address the resulting terminological inconsistency by proposing a refined, mechanism-based definition of MFM centered on its identity as a "Z-disk-opathy." This re-evaluation is timely and relevant for improving diagnostic clarity and guiding future research.

Genotype-phenotype correlation in recessive DNAJB4 myopathy.

Protein aggregate myopathies can result from pathogenic variants in genes encoding protein chaperones. DNAJB4 is a cochaperone belonging to the heat shock protein-40 (HSP40) family and plays a vital role in cellular proteostasis. Recessive loss-of-function variants in cause myopathy with early respiratory failure and spinal rigidity, presenting from infancy to adulthood.

Genotype‒phenotype correlation in recessive DNAJB4 myopathy.

Protein aggregate myopathies can result from pathogenic variants in genes encoding protein chaperones. DNAJB4 is a cochaperone belonging to the heat shock protein-40 (HSP40) family and plays a vital role in cellular proteostasis. Recessive loss-of-function variants in DNAJB4 cause myopathy with early respiratory failure and spinal rigidity, presenting from infancy to adulthood.

Clinical Classification of Variants in the Valosin-Containing Protein Gene Associated With Multisystem Proteinopathy.

Background And Objectives: Pathogenic variants in the valosin-containing protein () gene cause a phenotypically heterogeneous disorder that includes myopathy, motor neuron disease, Paget disease of the bone, frontotemporal dementia, and parkinsonism termed multisystem proteinopathy. This hallmark pleiotropy makes the classification of novel variants challenging. This retrospective study describes and assesses the effect of 19 novel or nonpreviously clinically characterized variants identified in 28 patients (26 unrelated families) in the retrospective VCP International Multicenter Study.

Cryo-EM structures of human zinc transporter ZnT7 reveal the mechanism of Zn uptake into the Golgi apparatus.

Zinc ions (Zn) are vital to most cells, with the intracellular concentrations of Zn being tightly regulated by multiple zinc transporters located at the plasma and organelle membranes. We herein present the 2.2-3.

The oxidative folding of nascent polypeptides provides electrons for reductive reactions in the ER.

The endoplasmic reticulum (ER) maintains an oxidative redox environment that is advantageous for the oxidative folding of nascent polypeptides entering the ER. Reductive reactions within the ER are also crucial for maintaining ER homeostasis. However, the mechanism by which electrons are supplied for the reductase activity within the ER remains unknown.

Association Between HLA Alleles and Autoantibodies in Dermatomyositis Defined by Sarcoplasmic Expression of Myxovirus Resistance Protein A.

Objective: The diagnosis in the studies analyzing HLA of dermatomyositis (DM) was based on a combined clinical category of polymyositis/DM. This retrospective study investigated the associations of HLA with 5 DM-specific autoantibodies in Japanese patients diagnosed by muscle pathology.

Methods: We diagnosed Japanese patients with DM based on sarcoplasmic expression of myxovirus resistance protein A.

A Case of Cardiogenic Stroke With a Novel LMNA Variant (c. 1135C>A; p.Leu379Ile).

Laminopathy is muscular dystrophy caused by an gene mutation. It is characterized by cardiac disease such as atrial fibrillation. We report a case of laminopathy in a 49-year-old woman who presented with cardiogenic stroke.

Muscle pathology of antisynthetase syndrome according to antibody subtypes.

Identification of antisynthetase syndrome (ASS) could be challenging due to inaccessibility and technical difficulty of the serology test for the less common non-Jo-1 antibodies. This study aimed to describe ASS antibody-specific myopathology and evaluate the diagnostic utility of myofiber HLA-DR expression. We reviewed 212 ASS muscle biopsies and compared myopathologic features among subtypes.

Cryo-EM structures of human SPCA1a reveal the mechanism of Ca/Mn transport into the Golgi apparatus.

Secretory pathway Ca/Mn ATPase 1 (SPCA1) actively transports cytosolic Ca and Mn into the Golgi lumen, playing a crucial role in cellular calcium and manganese homeostasis. Detrimental mutations of the gene encoding SPCA1 cause Hailey-Hailey disease. Here, using nanobody/megabody technologies, we determined cryo-electron microscopy structures of human SPCA1a in the ATP and Ca/Mn-bound (E1-ATP) state and the metal-free phosphorylated (E2P) state at 3.

Distinctive chaperonopathy in skeletal muscle associated with the dominant variant in DNAJB4.

DnaJ homolog, subfamily B, member 4, a member of the heat shock protein 40 chaperones encoded by DNAJB4, is highly expressed in myofibers. We identified a heterozygous c.270 T > A (p.

Hepatic veno-occlusive disease accompanied by thrombotic microangiopathy developed during treatment of juvenile dermatomyositis and macrophage activation syndrome: A case report.

Hepatic veno-occlusive disease (VOD) is a complication of haematopoietic stem cell transplantation. VOD is associated with the occurrence of thrombotic microangiopathy (TMA). In haematopoietic stem cell transplantation, VOD and TMA are endothelial syndromes resulting from endothelial cell activation and dysfunction.

Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure.

DNAJ/HSP40 co-chaperones are integral to the chaperone network, bind client proteins and recruit them to HSP70 for folding. We performed exome sequencing on patients with a presumed hereditary muscle disease and no genetic diagnosis. This identified four individuals from three unrelated families carrying an unreported homozygous stop gain (c.

Myoglobinopathy affecting facial and oropharyngeal muscles.

Myoglobinopathy is a rare autosomal dominant myopathy that manifests in adulthood with proximal and axial weakness and variable respiratory and cardiac failure. Muscle pathology features associated with myoglobinopathy include characteristic sarcoplasmic bodies in skeletal and cardiac muscles. Here we present the first case of myoglobinopathy in an Asian individual.

Reliability of antinuclear matrix protein 2 antibody assays in idiopathic inflammatory myopathies is dependent on target protein properties.

A line blotting assay (LB) is currently used to detect myositis-specific autoantibodies (MSAs) in patients with idiopathic inflammatory myopathies (IIMs), because of its simplicity; however, the sensitivity and specificity of this assay is low. The aim of this study is to evaluate the accuracy of the commercial LB in detection of antinuclear matrix protein 2 (NXP2) antibody. Seventy-seven serum samples from patients with IIMs, in which anti-NXP2 antibodies were detected through immunoprecipitation and western blotting (IP-WB) using K562 cell lysate, were enrolled.

Dermatomyositis: Muscle Pathology According to Antibody Subtypes.

Background And Objectives: Discoveries of dermatomyositis-specific antibodies (DMSAs) in patients with dermatomyositis raised awareness of various myopathologic features among antibody subtypes. However, only perifascicular atrophy and perifascicular myxovirus resistant protein A (MxA) overexpression were officially included as definitive pathologic criteria for dermatomyositis classification. We aimed to demonstrate myopathologic features in MxA-positive dermatomyositis to determine characteristic myopathologic features in different DMSA subtypes.

Clinical trajectory of a patient with filaminopathy who developed arrhythmogenic cardiomyopathy, myofibrillar myopathy, and multiorgan tumors.

We report a case of a patient presenting with arrhythmogenic cardiomyopathy, myofibrillar myopathy, and multiorgan tumors. A 41-year-old woman with a history of hypertrophic cardiomyopathy, diagnosed at 6 years of age, developed scoliosis after puberty. Following spinal surgery to address the scoliosis, she developed recurrent severe arrhythmia and heart failure.

Mild form of Danon disease: two case reports.

Danon disease is typically lethal by the mid-twenties in male patients due to cardiomyopathy. This report aims to describe two unrelated male patients showing mild manifestations of the disease. A 39-year-old man presented with a 10-year history of elevated serum creatine kinase levels with slowly progressive muscle weakness.

Deep convolutional neural network-based algorithm for muscle biopsy diagnosis.

Histopathologic evaluation of muscle biopsy samples is essential for classifying and diagnosing muscle diseases. However, the numbers of experienced specialists and pathologists are limited. Although new technologies such as artificial intelligence are expected to improve medical reach, their use with rare diseases, such as muscle diseases, is challenging because of the limited availability of training datasets.

MLIP causes recessive myopathy with rhabdomyolysis, myalgia and baseline elevated serum creatine kinase.

Striated muscle needs to maintain cellular homeostasis in adaptation to increases in physiological and metabolic demands. Failure to do so can result in rhabdomyolysis. The identification of novel genetic conditions associated with rhabdomyolysis helps to shed light on hitherto unrecognized homeostatic mechanisms.