Mutations In MATR3 Research Articles

Nationwide survey of patients with multisystem proteinopathy in Japan.

Multisystem proteinopathy (MSP) is an inherited disorder in which protein aggregates with TAR DNA-binding protein of 43 kDa form in multiple organs. Mutations in VCP, HNRNPA2B1, HNRNPA1, SQSTM1, MATR3, and ANXA11 are causative for MSP. This study aimed to conduct a nationwide epidemiological survey based on the diagnostic criteria established by the Japan MSP study group. We conducted a nationwide epidemiological survey by administering primary and secondary questionnaires among 6235 specialists of the Japanese Society of Neurology. In the primary survey, 47 patients with MSP were identified. In the secondary survey of 27 patients, inclusion body myopathy was the most common initial symptom (74.1%), followed by motor neuron disease (11.1%), frontotemporal dementia (FTD, 7.4%), and Paget's disease of bone (PDB, 7.4%), with no cases of parkinsonism. Inclusion body myopathy occurred most frequently during the entire course of the disease (81.5%), followed by motor neuron disease (25.9%), PDB (18.5%), FTD (14.8%), and parkinsonism (3.7%). Laboratory findings showed a high frequency of elevated serum creatine kinase levels and abnormalities on needle electromyography, muscle histology, brain magnetic resonance imaging, and perfusion single-photon emission computed tomography. The low frequency of FTD and PDB may suggest that FTD and PDB may be widely underdiagnosed and undertreated in clinical practice.

MATR3 P154S knock-in mice do not exhibit motor, muscle or neuropathologic features of ALS

MATR3 P154S knock-in mice do not exhibit motor, muscle or neuropathologic features of ALS

Expanding the Phenotypic Spectrum of Vocal Cord and Pharyngeal Weakness With Distal Myopathy due to the p.S85C MATR3 Mutation.

ObjectivesThe c.254C>G (p.S85C) MATR3 variant causes vocal cord and pharyngeal weakness with distal myopathy (VCPDM), which is characterized by progressive, asymmetric, predominantly distal muscle weakness, dysphonia, dysphagia, and respiratory impairment. Herein, we describe an Italian patient who harbored the p.S85C MATR3 variant and showed a composite phenotype of VCPDM and sensorimotor polyneuropathy.MethodsThe proband underwent neurologic evaluation, muscular MRI of the lower limbs, neurophysiologic assessment, muscle biopsy, and spirometry. After excluding common acquired and genetic causes of sensorimotor polyneuropathy, a larger group of genes involved in inherited forms of neuropathy, distal myopathy, and motor neuron disorders were analyzed by next-generation sequencing targeted panels.ResultsThe patient, affected by progressive distal muscle weakness and hypotrophy, myalgias, dysphonia, dysphagia, respiratory impairment, and sensory abnormalities, harbored the heterozygous c.254C>G (p.S85C) MATR3 substitution. Neurophysiologic assessment revealed a severe sensorimotor polyneuropathy. Variation of fiber size, central nuclei, and nonrimmed vacuoles were evident at muscle biopsy.DiscussionThis finding extends the MATR3-associated VCPDM phenotypic spectrum and suggests considering MATR3 analysis in suspected congenital polyneuropathies with odd features, including dysphonia, dysphagia, and respiratory insufficiency.

Selective Loss of MATR3 in Spinal Interneurons, Upper Motor Neurons and Hippocampal CA1 Neurons in a MATR3 S85C Knock-In Mouse Model of Amyotrophic Lateral Sclerosis.

Simple SummaryAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the motor neurons in the brain and spinal cord. Mutations in the gene Matr3 have been linked to ALS, including the autosomal dominant missense mutation S85C. We previously created a mouse model containing the S85C mutation in the Matr3 gene to understand how it causes ALS. The S85C mice exhibited MATR3 staining loss in selective populations of degenerating neurons, such as Purkinje cells in the cerebellum and α-motor neurons in the lumbar spinal cord. However, studies have shown that neurons other than motor neurons may be involved in contributing to ALS; therefore, we investigated additional neuronal cell types in the spinal cord and brain. Here, we found that MATR3 staining is selectively reduced in interneurons and α-motor neurons of the cervical and thoracic regions of the spinal cord, as well as in subsets of upper motor neurons and hippocampal neurons. These neurons did not exhibit cell body loss; however, how the MATR3 loss affects neuronal function remains to be determined. Overall, these findings demonstrate that the MATR3 S85C mutation affects other neuronal types of the brain and spinal cord in addition to motor neurons, suggesting that these additional neuronal types are involved in ALS pathogenesis.The neuropathological hallmark of amyotrophic lateral sclerosis (ALS) is motor neuron degeneration in the spinal cord and cortex. Accumulating studies report that other neurons in the central nervous system (CNS) are also affected in ALS. Mutations in Matr3, which encodes a nuclear matrix protein involved in RNA splicing, have been linked to ALS. Previously, we generated a MATR3 S85C knock-in (KI) mouse model that recapitulates early-stage features of ALS. We reported that MATR3 S85C KI mice exhibit defects in lumbar spinal cord motor neurons and in cerebellar Purkinje cells, which are associated with reduced MATR3 immunoreactivity. Here, we show that neurons in various other regions of the CNS are affected in MATR3 S85C KI mice. Using histological analyses, we found selective loss of MATR3 staining in α-motor neurons, but not γ-motor neurons in the cervical and thoracic spinal cord. Loss of MATR3 was also found in parvalbumin-positive interneurons in the cervical, thoracic and lumbar spinal cord. In addition, we found the loss of MATR3 in subsets of upper motor neurons and hippocampal CA1 neurons. Collectively, our findings suggest that these additional neuronal types may contribute to the disease process in MATR3 S85C KI mice.

Molecular determinants and modifiers of Matrin-3 toxicity, condensate dynamics, and droplet morphology

Molecular determinants and modifiers of Matrin-3 toxicity, condensate dynamics, and droplet morphology

Matrin3: Disorder and ALS Pathogenesis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the degeneration of both upper and lower motor neurons in the brain and spinal cord. ALS is associated with protein misfolding and inclusion formation involving RNA-binding proteins, including TAR DNA-binding protein (TDP-43) and fused in sarcoma (FUS). The 125-kDa Matrin3 is a highly conserved nuclear DNA/RNA-binding protein that is implicated in many cellular processes, including binding and stabilizing mRNA, regulating mRNA nuclear export, modulating alternative splicing, and managing chromosomal distribution. Mutations in MATR3, the gene encoding Matrin3, have been identified as causal in familial ALS (fALS). Matrin3 lacks a prion-like domain that characterizes many other ALS-associated RNA-binding proteins, including TDP-43 and FUS, however, our bioinformatics analyses and preliminary studies document that Matrin3 contains long intrinsically disordered regions that may facilitate promiscuous interactions with many proteins and may contribute to its misfolding. In addition, these disordered regions in Matrin3 undergo numerous post-translational modifications, including phosphorylation, ubiquitination and acetylation that modulate the function and misfolding of the protein. Here we discuss the disordered nature of Matrin3 and review the factors that may promote its misfolding and aggregation, two elements that might explain its role in ALS pathogenesis.

ALS Associated Mutations in Matrin 3 Alter Protein-Protein Interactions and Impede mRNA Nuclear Export

Mutations in Matrin 3 have recently been linked to ALS, though the mechanism that induces disease in these patients is unknown. To define the protein interactome of wild-type and ALS-linked MATR3 mutations, we performed immunoprecipitation followed by mass spectrometry using NSC-34 cells expressing human wild-type or mutant Matrin 3. Gene ontology analysis identified a novel role for Matrin 3 in mRNA transport centered on proteins in the TRanscription and EXport (TREX) complex, known to function in mRNA biogenesis and nuclear export. ALS-linked mutations in Matrin 3 led to its re-distribution within the nucleus, decreased co-localization with endogenous Matrin 3 and increased co-localization with specific TREX components. Expression of disease-causing Matrin 3 mutations led to nuclear mRNA export defects of both global mRNA and more specifically the mRNA of TDP-43 and FUS. Our findings identify a potential pathogenic mechanism attributable to MATR3 mutations and further link cellular transport defects to ALS.

Investigating CCNF mutations in a Taiwanese cohort with amyotrophic lateral sclerosis

Investigating CCNF mutations in a Taiwanese cohort with amyotrophic lateral sclerosis

Heterogeneity of Matrin 3 in the developing and aging murine central nervous system.

Mutations in the MATR3 gene encoding the nucleotide binding protein Matrin 3 have recently been identified as causing a subset of familial amyotrophic lateral sclerosis (fALS) and more rarely causing distal myopathy. Translating the identification of MATR3 mutations into an understanding of disease pathogenesis and the creation of mouse models requires a complete understanding of normal Matrin 3 levels and distribution in vivo. Consequently, we examined the levels of murine Matrin 3 in body tissues and regions of the central nervous system (CNS). We observed a significant degree of variability in Matrin 3 protein levels among different tissues of adult animals, with the highest levels found in reproductive organs and the lowest in muscle. Within the adult CNS, Matrin 3 levels were lowest in spinal cord. Further, we found that Matrin 3 declines significantly in CNS through early development and young adulthood before stabilizing. As previously reported, antibodies to Matrin 3 primarily stain nuclei, but the intensity of staining was not uniform in all nuclei. The low levels of Matrin 3 in spinal cord and muscle could mean that that these tissues are particularly vulnerable to alterations in Matrin 3 function. Our study is the first to characterize endogenous Matrin 3 in rodents across the lifespan, providing the groundwork for deciphering disease mechanisms and developing mouse models of MATR3-linked ALS. J. Comp. Neurol. 524:2740-2752, 2016. © 2016 Wiley Periodicals, Inc.

Mutational analysis of TBK1 in Taiwanese patients with amyotrophic lateral sclerosis

Mutational analysis of TBK1 in Taiwanese patients with amyotrophic lateral sclerosis

MATR3 mutation analysis in a Chinese cohort with sporadic amyotrophic lateral sclerosis

MATR3 mutation analysis in a Chinese cohort with sporadic amyotrophic lateral sclerosis

Replication study of MATR3 in familial and sporadic amyotrophic lateral sclerosis

Replication study of MATR3 in familial and sporadic amyotrophic lateral sclerosis

What's in the Literature?

In this issue, we review new information related to amyotrophic lateral sclerosis, diagnostic testing practices, differences in clinical management between patients seen in multidisciplinary and regular clinics, and managing end-of-life care issues. There is new information on genes and genetic risk factors and environmental risk factors. There are 2 other forms of motor neuron disease, progressive muscular atrophy, and spinal muscular atrophy that are also considered. Inflammatory neuropathies are important to identify as they can be treated. Ultrasound is being applied to the diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy, but its utility is more likely supportive than as a stand-alone test. There is some evidence that follow-up nerve conduction studies can reveal patients with chronic inflammatory demyelinating polyradiculoneuropathy who might relapse if intravenous immunoglobulin is stopped. The spectrum of inflammatory neuropathies is broad and some may have focal pathology at the node of Ranvier, and the term “nodopathies” has been proposed to highlight this important region of the nerve. The diagnosis of hereditary neuropathies relies on gene testing, and data on the frequency of particular mutations show the utility of initial testing for 4 genes. Chemotherapeutic drugs can be toxic to nerves, and the incidence of neuropathies from bortezomib is discussed. The risk of development of diabetes mellitus in patients with myasthenia gravis (MG) is reviewed as is the risk of development of MG after thymectomy in patients who are asymptomatic preoperatively. A vaccine to “cure” MG has been tested in animal models. Recent work in Oxford has demonstrated direct evidence that antibodies from patients with Lambert–Eaton myasthenic syndrome acts directly on P/Q-type voltage-gated calcium channels to inhibit exocytosis of synaptic vesicles. The clinical and pathological features of myopathy associated with mutations in MATR-3 are reviewed. The natural history of myotonic dystrophy type 1 (DM1) is discussed as are potential therapies to treat myotonia in a number of disorders.

Impairment of respiratory function in late-onset distal myopathy due to MATR3 Mutation.

Recently, mutations in the MATR3 gene were found to cause late-onset distal myopathy. The frequency and impact of respiratory involvement are not clear. Respiratory parameters [maximum vital capacity (VCmax); forced expiratory volume (FEV1 ); peak expiratory flow (PEF), postural drop of VCmax from sitting to supine, maximum inspiratory muscle pressure (PImax), mouth occlusion pressure after 100 ms (P 0.1), peak cough flow, and blood-gas analysis] were monitored prospectively at baseline, and then 6 months and 12 months later in 8 patients with genetically confirmed MATR3 myopathy. All patients showed involvement of respiratory function. Six of 8 reported exertional dyspnea. At the end of follow-up, 5 of 8 had decreased VC, 7 of 8 had reduced PImax, and 5 of 7 had decreased partial pressure of oxygen (PO2 ). Within 12 months, respiratory parameters deteriorated non-significantly. No patient required non-invasive ventilation. There is a high risk of abnormal respiratory function with progressive worsening in MATR3 myopathy.

Mutational analysis of MATR3 in Taiwanese patients with amyotrophic lateral sclerosis

Mutational analysis of MATR3 in Taiwanese patients with amyotrophic lateral sclerosis

Phenotype of matrin-3-related distal myopathy in 16 German patients.

To characterize the phenotype of patients with distal myopathy with vocal cord and pharyngeal weakness due to the p.S85C mutation in the matrin-3 gene (MATR3, Mendelian Inheritance in Man 164015). Recently, it has been suggested that patients with this mutation may suffer from familial amyotrophic lateral sclerosis. Sixteen patients from 6 families with late onset distal myopathy associated with the p.S85C MATR3 mutation were characterized. Patients had a predominantly distal muscle weakness, most severely affecting ankle and wrist dorsiflexion. Relevant proximal and axial weakness was found in 6 and respiratory impairment in 5 patients. Dysphagia was diagnosed in 6 and mild voice abnormalities were found in 7 patients. However, laryngoscopy revealed normal vocal cord function. Creatine kinase was normal or mildly elevated. Electromyographically, spontaneous activity was found in 10 of 14 patients and complex repetitive discharges in 9 of 14 patients. Magnetic resonance imaging revealed severe fatty degeneration of distal and upper posterior leg and of paraspinal muscles. Histopathology ranged from mild myopathic to severe dystrophic changes including vacuoles. Absence of sarcomeres in the perinuclear region and abnormal invaginations of nuclei were found ultrastructurally. Haplotype analysis showed a common disease-specific haplotype of the 6 families and suggested that these families form a separate cluster. In contrast to the 2 previously reported families, MATR3-related distal myopathy might be associated with relevant axial, proximal, and respiratory muscle weakness but without vocal cord palsy. There were no clinical, electrophysiological, or histopathological signs of lower motor neuron involvement.

Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis.

MATR3 is an RNA/DNA binding protein that interacts with TDP-43, a major disease protein linked to amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia. Using exome sequencing, we identified mutations in MATR3 in ALS kindreds. We also observed MATR3 pathology in the spinal cords of ALS cases with and without MATR3 mutations. Our data provide additional evidence supporting the role of aberrant RNA processing in motor neuron degeneration.

A study of FHL1, BAG3, MATR3, PTRF and TCAP in Australian muscular dystrophy patients

A study of FHL1, BAG3, MATR3, PTRF and TCAP in Australian muscular dystrophy patients