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Nigel G Laing - One of the best experts on this subject based on the ideXlab platform.
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Generation of two isogenic induced pluripotent stem cell lines from a 10-year-old typical nemaline myopathy patient with a heterozygous dominant c.541G>A (p.Asp179Asn) pathogenic variant in the ACTA1 gene
'Elsevier BV', 2021Co-Authors: Joshua S. Clayton, Norma B Romero, Nigel G Laing, Kristen J Nowak, Edoardo Malfatti, Carolin K. Scriba, Safaa Saker, Thierry Larmonier, Gianina Ravenscroft, Rhonda L. TaylorAbstract:Nemaline myopathy (NM) is a congenital myopathy typically characterized by skeletal muscle weakness and the presence of nemaline bodies in myofibres. Approximately 25% of NM cases are caused by variants in ACTA1. We generated two induced pluripotent stem cell lines from lymphoblastoid cells of a 10-year-old female with typical NM harbouring a dominant pathogenic variant in ACTA1 (c.541C>A). The isogenic lines displayed typical iPSC morphology, expressed pluripotency markers, and could differentiate into each of the three germ layers. Although the lines have partial or complete X chromosome duplication, they may still prove useful as models of human ACTA1 disease
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actin myopathy with nemaline bodies intranuclear rods and a heterozygous mutation in acta1 asp154asn
Acta Neuropathologica, 2004Co-Authors: J M Schroder, Hayley J Durling, Nigel G LaingAbstract:Mutations in the skeletal muscle α-actin gene (ACTA1) are associated by and large with three muscle diseases (1) congenital actin myopathy, (2) nemaline myopathy, and (3) intranuclear rod myopathy. More than 70 mutations have now been identified. The majority of ACTA1 mutations are dominant, a small number are recessive and most isolated cases with no previous family history have de novo dominant mutations. The present case, a boy of healthy Turkish parents, had a severe form of the disease of the latter type due to a heterozygous, presumably de novo mutation of the ACTA1 gene in exon 4 (Asp154Asn), with lack of spontaneous movements at birth requiring immediate mechanical ventilation. He died at the age of 9 weeks due to respiratory failure, secondary pneumonia, and chylothorax. The biopsy specimen of the femoral muscle was characterized by pleomorphic alterations with numerous muscle fibers showing accumulation of actin filaments, but, in addition, both nemaline bodies and intranuclear rod bodies. This was also seen in several other muscles investigated at autopsy. No developmental abnormalities of the central nervous system, and no loss of spinal motor neurons were detected despite atrophy or hypotrophy of a considerable number of muscle fibers. The peripheral nervous system, which has not been studied before in patients with ACTA1 mutations, showed no loss of motor or sensory myelinated fibers and no loss of sensory neurons in spinal ganglia.
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muscle disease caused by mutations in the skeletal muscle alpha actin gene acta1
Neuromuscular Disorders, 2003Co-Authors: John C Sparrow, Hayley J Durling, Carina Wallgrenpettersson, Norma B Romero, Alan H Beggs, Kristen J Nowak, Ikuya Nonaka, Nigel G LaingAbstract:Mutations in the skeletal muscle alpha-actin gene (ACTA1) associated with congenital myopathy with excess of thin myofilaments, nemaline myopathy and intranuclear rod myopathy were first described in 1999. At that time, only 15 different missense mutations were known in ACTA1. More than 60 mutations have now been identified. This review analyses this larger spectrum of mutations in ACTA1. It investigates the molecular consequences of the mutations found to date, provides a framework for genotype ‐phenotype correlation and suggests future studies in light of results of investigation of normal and mutant actin in other systems, notably the actin specific to the indirect flight muscles of Drosophila. The larger series confirms that the majority of ACTA1 mutations are dominant, a small number are recessive and most isolated cases with no previous family history have de novo dominant mutations. The severity of the disease caused ranges from lack of spontaneous movements at birth requiring immediate mechanical ventilation, to mild disease compatible with life to adulthood. Overall, the mutations within ACTA1 are randomly distributed throughout the protein. However, the larger series of mutations now available indicates that there may be clustering of mutations associated with some phenotypes, e.g. actin myopathy. This would suggest that interference with certain actin functions may be more associated with certain phenotypes, though the exact pathophysiology of the actin mutations remains unknown. q 2003 Elsevier B.V. All rights reserved.
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muscle disease caused by mutations in the skeletal muscle alpha actin gene acta1
Neuromuscular Disorders, 2003Co-Authors: John C Sparrow, Hayley J Durling, Carina Wallgrenpettersson, Norma B Romero, Alan H Beggs, Kristen J Nowak, Ikuya Nonaka, Nigel G LaingAbstract:Mutations in the skeletal muscle alpha-actin gene (ACTA1) associated with congenital myopathy with excess of thin myofilaments, nemaline myopathy and intranuclear rod myopathy were first described in 1999. At that time, only 15 different missense mutations were known in ACTA1. More than 60 mutations have now been identified. This review analyses this larger spectrum of mutations in ACTA1. It investigates the molecular consequences of the mutations found to date, provides a framework for genotype ‐phenotype correlation and suggests future studies in light of results of investigation of normal and mutant actin in other systems, notably the actin specific to the indirect flight muscles of Drosophila. The larger series confirms that the majority of ACTA1 mutations are dominant, a small number are recessive and most isolated cases with no previous family history have de novo dominant mutations. The severity of the disease caused ranges from lack of spontaneous movements at birth requiring immediate mechanical ventilation, to mild disease compatible with life to adulthood. Overall, the mutations within ACTA1 are randomly distributed throughout the protein. However, the larger series of mutations now available indicates that there may be clustering of mutations associated with some phenotypes, e.g. actin myopathy. This would suggest that interference with certain actin functions may be more associated with certain phenotypes, though the exact pathophysiology of the actin mutations remains unknown. q 2003 Elsevier B.V. All rights reserved.
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muscle disease caused by mutations in the skeletal muscle alpha actin gene acta1
Neuromuscular Disorders, 2003Co-Authors: John C Sparrow, Hayley J Durling, Carina Wallgrenpettersson, Norma B Romero, Alan H Beggs, Kristen J Nowak, Ikuya Nonaka, Nigel G LaingAbstract:Mutations in the skeletal muscle alpha-actin gene (ACTA1) associated with congenital myopathy with excess of thin myofilaments, nemaline myopathy and intranuclear rod myopathy were first described in 1999. At that time, only 15 different missense mutations were known in ACTA1. More than 60 mutations have now been identified. This review analyses this larger spectrum of mutations in ACTA1. It investigates the molecular consequences of the mutations found to date, provides a framework for genotype-phenotype correlation and suggests future studies in light of results of investigation of normal and mutant actin in other systems, notably the actin specific to the indirect flight muscles of Drosophila. The larger series confirms that the majority of ACTA1 mutations are dominant, a small number are recessive and most isolated cases with no previous family history have de novo dominant mutations. The severity of the disease caused ranges from lack of spontaneous movements at birth requiring immediate mechanical ventilation, to mild disease compatible with life to adulthood. Overall, the mutations within ACTA1 are randomly distributed throughout the protein. However, the larger series of mutations now available indicates that there may be clustering of mutations associated with some phenotypes, e.g. actin myopathy. This would suggest that interference with certain actin functions may be more associated with certain phenotypes, though the exact pathophysiology of the actin mutations remains unknown.
Kristen J Nowak - One of the best experts on this subject based on the ideXlab platform.
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Generation of two isogenic induced pluripotent stem cell lines from a 10-year-old typical nemaline myopathy patient with a heterozygous dominant c.541G>A (p.Asp179Asn) pathogenic variant in the ACTA1 gene
'Elsevier BV', 2021Co-Authors: Joshua S. Clayton, Norma B Romero, Nigel G Laing, Kristen J Nowak, Edoardo Malfatti, Carolin K. Scriba, Safaa Saker, Thierry Larmonier, Gianina Ravenscroft, Rhonda L. TaylorAbstract:Nemaline myopathy (NM) is a congenital myopathy typically characterized by skeletal muscle weakness and the presence of nemaline bodies in myofibres. Approximately 25% of NM cases are caused by variants in ACTA1. We generated two induced pluripotent stem cell lines from lymphoblastoid cells of a 10-year-old female with typical NM harbouring a dominant pathogenic variant in ACTA1 (c.541C>A). The isogenic lines displayed typical iPSC morphology, expressed pluripotency markers, and could differentiate into each of the three germ layers. Although the lines have partial or complete X chromosome duplication, they may still prove useful as models of human ACTA1 disease
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multimodal mri and 31p mrs investigations of the acta1 asp286gly mouse model of nemaline myopathy provide evidence of impaired in vivo muscle function altered muscle structure and disturbed energy metabolism
PLOS ONE, 2013Co-Authors: Charlotte Gineste, Kristen J Nowak, Guillaume Duhamel, Christophe Vilmen, Patrick J. Cozzone, David Bendahan, Julien GondinAbstract:Nemaline myopathy (NM), the most common non-dystrophic congenital disease of skeletal muscle, can be caused by mutations in the skeletal muscle α-actin gene (ACTA1) (~25% of all NM cases and up to 50% of severe forms of NM). Muscle function of the recently generated transgenic mouse model carrying the human Asp286Gly mutation in the ACTA1 gene (Tg(ACTA1)Asp286Gly) has been mainly investigated in vitro. Therefore, we aimed at providing a comprehensive picture of the in vivo hindlimb muscle function of Tg(ACTA1)Asp286Gly mice by combining strictly noninvasive investigations. Skeletal muscle anatomy (hindlimb muscles, intramuscular fat volumes) and microstructure were studied using multimodal magnetic resonance imaging (Dixon, T2, Diffusion Tensor Imaging [DTI]). Energy metabolism was studied using 31-phosphorus Magnetic Resonance Spectroscopy (31P-MRS). Skeletal muscle contractile performance was investigated while applying a force-frequency protocol (1–150 Hz) and a fatigue protocol (6 min–1.7 Hz). Tg(ACTA1)Asp286Gly mice showed a mild muscle weakness as illustrated by the reduction of both absolute (30%) and specific (15%) maximal force production. Dixon MRI did not show discernable fatty infiltration in Tg(ACTA1)Asp286Gly mice indicating that this mouse model does not reproduce human MRI findings. Increased T2 values were observed in Tg(ACTA1)Asp286Gly mice and might reflect the occurrence of muscle degeneration/regeneration process. Interestingly, T2 values were linearly related to muscle weakness. DTI experiments indicated lower λ2 and λ3 values in Tg(ACTA1)Asp286Gly mice, which might be associated to muscle atrophy and/or the presence of histological anomalies. Finally 31P-MRS investigations illustrated an increased anaerobic energy cost of contraction in Tg(ACTA1)Asp286Gly mice, which might be ascribed to contractile and non-contractile processes. Overall, we provide a unique set of information about the anatomic, metabolic and functional consequences of the Asp286Gly mutation that might be considered as relevant biomarkers for monitoring the severity and/or the progression of NM and for assessing the efficacy of potential therapeutic interventions.
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muscle disease caused by mutations in the skeletal muscle alpha actin gene acta1
Neuromuscular Disorders, 2003Co-Authors: John C Sparrow, Hayley J Durling, Carina Wallgrenpettersson, Norma B Romero, Alan H Beggs, Kristen J Nowak, Ikuya Nonaka, Nigel G LaingAbstract:Mutations in the skeletal muscle alpha-actin gene (ACTA1) associated with congenital myopathy with excess of thin myofilaments, nemaline myopathy and intranuclear rod myopathy were first described in 1999. At that time, only 15 different missense mutations were known in ACTA1. More than 60 mutations have now been identified. This review analyses this larger spectrum of mutations in ACTA1. It investigates the molecular consequences of the mutations found to date, provides a framework for genotype ‐phenotype correlation and suggests future studies in light of results of investigation of normal and mutant actin in other systems, notably the actin specific to the indirect flight muscles of Drosophila. The larger series confirms that the majority of ACTA1 mutations are dominant, a small number are recessive and most isolated cases with no previous family history have de novo dominant mutations. The severity of the disease caused ranges from lack of spontaneous movements at birth requiring immediate mechanical ventilation, to mild disease compatible with life to adulthood. Overall, the mutations within ACTA1 are randomly distributed throughout the protein. However, the larger series of mutations now available indicates that there may be clustering of mutations associated with some phenotypes, e.g. actin myopathy. This would suggest that interference with certain actin functions may be more associated with certain phenotypes, though the exact pathophysiology of the actin mutations remains unknown. q 2003 Elsevier B.V. All rights reserved.
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muscle disease caused by mutations in the skeletal muscle alpha actin gene acta1
Neuromuscular Disorders, 2003Co-Authors: John C Sparrow, Hayley J Durling, Carina Wallgrenpettersson, Norma B Romero, Alan H Beggs, Kristen J Nowak, Ikuya Nonaka, Nigel G LaingAbstract:Mutations in the skeletal muscle alpha-actin gene (ACTA1) associated with congenital myopathy with excess of thin myofilaments, nemaline myopathy and intranuclear rod myopathy were first described in 1999. At that time, only 15 different missense mutations were known in ACTA1. More than 60 mutations have now been identified. This review analyses this larger spectrum of mutations in ACTA1. It investigates the molecular consequences of the mutations found to date, provides a framework for genotype ‐phenotype correlation and suggests future studies in light of results of investigation of normal and mutant actin in other systems, notably the actin specific to the indirect flight muscles of Drosophila. The larger series confirms that the majority of ACTA1 mutations are dominant, a small number are recessive and most isolated cases with no previous family history have de novo dominant mutations. The severity of the disease caused ranges from lack of spontaneous movements at birth requiring immediate mechanical ventilation, to mild disease compatible with life to adulthood. Overall, the mutations within ACTA1 are randomly distributed throughout the protein. However, the larger series of mutations now available indicates that there may be clustering of mutations associated with some phenotypes, e.g. actin myopathy. This would suggest that interference with certain actin functions may be more associated with certain phenotypes, though the exact pathophysiology of the actin mutations remains unknown. q 2003 Elsevier B.V. All rights reserved.
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muscle disease caused by mutations in the skeletal muscle alpha actin gene acta1
Neuromuscular Disorders, 2003Co-Authors: John C Sparrow, Hayley J Durling, Carina Wallgrenpettersson, Norma B Romero, Alan H Beggs, Kristen J Nowak, Ikuya Nonaka, Nigel G LaingAbstract:Mutations in the skeletal muscle alpha-actin gene (ACTA1) associated with congenital myopathy with excess of thin myofilaments, nemaline myopathy and intranuclear rod myopathy were first described in 1999. At that time, only 15 different missense mutations were known in ACTA1. More than 60 mutations have now been identified. This review analyses this larger spectrum of mutations in ACTA1. It investigates the molecular consequences of the mutations found to date, provides a framework for genotype-phenotype correlation and suggests future studies in light of results of investigation of normal and mutant actin in other systems, notably the actin specific to the indirect flight muscles of Drosophila. The larger series confirms that the majority of ACTA1 mutations are dominant, a small number are recessive and most isolated cases with no previous family history have de novo dominant mutations. The severity of the disease caused ranges from lack of spontaneous movements at birth requiring immediate mechanical ventilation, to mild disease compatible with life to adulthood. Overall, the mutations within ACTA1 are randomly distributed throughout the protein. However, the larger series of mutations now available indicates that there may be clustering of mutations associated with some phenotypes, e.g. actin myopathy. This would suggest that interference with certain actin functions may be more associated with certain phenotypes, though the exact pathophysiology of the actin mutations remains unknown.
Alan H Beggs - One of the best experts on this subject based on the ideXlab platform.
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treatment with actriib mfc produces myofiber growth and improves lifespan in the acta1 h40y murine model of nemaline myopathy
American Journal of Pathology, 2016Co-Authors: Jennifer Tinklenberg, Alan H Beggs, Hui Meng, Lin Yang, Fujun Liu, Raymond G Hoffmann, Mahua Dasgupta, Kenneth P Allen, Edna C Hardeman, Scott R PearsallAbstract:Nemaline myopathies (NMs) are a group of congenital muscle diseases caused by mutations in at least 10 genes and associated with a range of clinical symptoms. NM is defined on muscle biopsy by the presence of cytoplasmic rod-like structures (nemaline rods) composed of cytoskeletal material. Myofiber smallness is also found in many cases of NM and may represent a cause of weakness that can be counteracted by treatment. We have used i.p. injection of activin type IIB receptor (ActRIIB)–mFc (an inhibitor of myostatin signaling) to promote hypertrophy and increase strength in our prior murine work; we therefore tested whether ActRIIB-mFc could improve weakness in NM mice through myofiber hypertrophy. We report a study of ActRIIB-mFc treatment in the Acta1 H40Y mouse model of NM. Treatment of Acta1 H40Y mice produced significant increases in body mass, muscle mass, quadriceps myofiber size, and survival, but other measurements of strength (forelimb grip strength, ex vivo measurements of contractile function) did not improve. Our studies also identified that the complications of urethral obstruction are associated with mortality in male hemizygote Acta1 H40Y mice. The incidence of urethral obstruction and histologic evidence of chronic obstruction (inflammation) were significantly lower in Acta1 H40Y mice that had been treated with ActRIIB-mFc. ActRIIB-mFc treatment produces a mild benefit to the disease phenotype in Acta1 H40Y mice.
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force sarcomere length relations in patients with thin filament myopathy caused by mutations in neb acta1 tpm2 tpm3 kbtbd13 klhl40 and klhl41
Biophysical Journal, 2015Co-Authors: Barbara Joureau, Alan H Beggs, N Romero, Josine M De Winter, Christopher T Pappas, Edoardo Malfatti, Nigel F Clarke, Carol C Gregorio, Henk GranzierAbstract:Background: Mutations in NEB, ACTA1, TPM2, TPM3, KBTBD13, KLHL40 and −41 lead to thin filament myopathies, such as nemaline myopathy, congenital fiber type disproportion and cap disease. A hallmark feature of these myopathies is muscle weakness. Here, we aimed to elucidate whether mutations in NEB, ACTA1, TPM2, TPM3, KBTBD13, KLHL40 and KLHL41 affect the maximal force generating capacity of muscle fibers. Subsequently, by determining the sarcomere length-dependence of force, we investigated whether changes in thin filament length contributed to muscle weakness.Methods: Biopsies from NM, CFTD, and CAP patients (n=39) with mutations in NEB, ACTA1, TPM2, TPM3, KBTBD13, KLHL40 or KLHL41 were compared to biopsies from healthy controls (n=9). Using permeabilized muscle fibers, maximal active tension was determined at incremental sarcomere lengths (range 2.0-3.5 µm) to obtain the force-sarcomere length relationship.Results: The maximal active tension (Fmax (in mN/mm2, mean±SEM)) was significantly lower in biopsies from NEB (46±5), ACTA1 (48±4), TPM2 (71±8), TPM3 (85±10), KBTBD13 (78±3), KLHL40 (2.8±0.2) and KLHL41 (63±4) patients compared to biopsies of controls (129±7).No shift in the force-sarcomere length relationship was observed in TPM3, TPM2, KBTBD 13, KLHL 40 and KLHL41 patients. In contrast, several patients with ACTA1 and NEB mutations showed a leftward shift of the force-sarcomere length relationship indicating shorter thin filaments. Furthermore, the slope of the descending limb of the force-sarcomere length relationship in these patients is less steep than the slope of the CTRL curve, suggesting heterogeneity of thin filaments.Conclusion: Our data suggest that mutations in NEB and ACTA1 result in changes in thin filament length. Insights in the mechanisms underlying weakness in patients with thin filament mutations are necessary to improve specific treatment strategies.
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muscle disease caused by mutations in the skeletal muscle alpha actin gene acta1
Neuromuscular Disorders, 2003Co-Authors: John C Sparrow, Hayley J Durling, Carina Wallgrenpettersson, Norma B Romero, Alan H Beggs, Kristen J Nowak, Ikuya Nonaka, Nigel G LaingAbstract:Mutations in the skeletal muscle alpha-actin gene (ACTA1) associated with congenital myopathy with excess of thin myofilaments, nemaline myopathy and intranuclear rod myopathy were first described in 1999. At that time, only 15 different missense mutations were known in ACTA1. More than 60 mutations have now been identified. This review analyses this larger spectrum of mutations in ACTA1. It investigates the molecular consequences of the mutations found to date, provides a framework for genotype ‐phenotype correlation and suggests future studies in light of results of investigation of normal and mutant actin in other systems, notably the actin specific to the indirect flight muscles of Drosophila. The larger series confirms that the majority of ACTA1 mutations are dominant, a small number are recessive and most isolated cases with no previous family history have de novo dominant mutations. The severity of the disease caused ranges from lack of spontaneous movements at birth requiring immediate mechanical ventilation, to mild disease compatible with life to adulthood. Overall, the mutations within ACTA1 are randomly distributed throughout the protein. However, the larger series of mutations now available indicates that there may be clustering of mutations associated with some phenotypes, e.g. actin myopathy. This would suggest that interference with certain actin functions may be more associated with certain phenotypes, though the exact pathophysiology of the actin mutations remains unknown. q 2003 Elsevier B.V. All rights reserved.
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muscle disease caused by mutations in the skeletal muscle alpha actin gene acta1
Neuromuscular Disorders, 2003Co-Authors: John C Sparrow, Hayley J Durling, Carina Wallgrenpettersson, Norma B Romero, Alan H Beggs, Kristen J Nowak, Ikuya Nonaka, Nigel G LaingAbstract:Mutations in the skeletal muscle alpha-actin gene (ACTA1) associated with congenital myopathy with excess of thin myofilaments, nemaline myopathy and intranuclear rod myopathy were first described in 1999. At that time, only 15 different missense mutations were known in ACTA1. More than 60 mutations have now been identified. This review analyses this larger spectrum of mutations in ACTA1. It investigates the molecular consequences of the mutations found to date, provides a framework for genotype ‐phenotype correlation and suggests future studies in light of results of investigation of normal and mutant actin in other systems, notably the actin specific to the indirect flight muscles of Drosophila. The larger series confirms that the majority of ACTA1 mutations are dominant, a small number are recessive and most isolated cases with no previous family history have de novo dominant mutations. The severity of the disease caused ranges from lack of spontaneous movements at birth requiring immediate mechanical ventilation, to mild disease compatible with life to adulthood. Overall, the mutations within ACTA1 are randomly distributed throughout the protein. However, the larger series of mutations now available indicates that there may be clustering of mutations associated with some phenotypes, e.g. actin myopathy. This would suggest that interference with certain actin functions may be more associated with certain phenotypes, though the exact pathophysiology of the actin mutations remains unknown. q 2003 Elsevier B.V. All rights reserved.
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muscle disease caused by mutations in the skeletal muscle alpha actin gene acta1
Neuromuscular Disorders, 2003Co-Authors: John C Sparrow, Hayley J Durling, Carina Wallgrenpettersson, Norma B Romero, Alan H Beggs, Kristen J Nowak, Ikuya Nonaka, Nigel G LaingAbstract:Mutations in the skeletal muscle alpha-actin gene (ACTA1) associated with congenital myopathy with excess of thin myofilaments, nemaline myopathy and intranuclear rod myopathy were first described in 1999. At that time, only 15 different missense mutations were known in ACTA1. More than 60 mutations have now been identified. This review analyses this larger spectrum of mutations in ACTA1. It investigates the molecular consequences of the mutations found to date, provides a framework for genotype-phenotype correlation and suggests future studies in light of results of investigation of normal and mutant actin in other systems, notably the actin specific to the indirect flight muscles of Drosophila. The larger series confirms that the majority of ACTA1 mutations are dominant, a small number are recessive and most isolated cases with no previous family history have de novo dominant mutations. The severity of the disease caused ranges from lack of spontaneous movements at birth requiring immediate mechanical ventilation, to mild disease compatible with life to adulthood. Overall, the mutations within ACTA1 are randomly distributed throughout the protein. However, the larger series of mutations now available indicates that there may be clustering of mutations associated with some phenotypes, e.g. actin myopathy. This would suggest that interference with certain actin functions may be more associated with certain phenotypes, though the exact pathophysiology of the actin mutations remains unknown.
John C Sparrow - One of the best experts on this subject based on the ideXlab platform.
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muscle disease caused by mutations in the skeletal muscle alpha actin gene acta1
Neuromuscular Disorders, 2003Co-Authors: John C Sparrow, Hayley J Durling, Carina Wallgrenpettersson, Norma B Romero, Alan H Beggs, Kristen J Nowak, Ikuya Nonaka, Nigel G LaingAbstract:Mutations in the skeletal muscle alpha-actin gene (ACTA1) associated with congenital myopathy with excess of thin myofilaments, nemaline myopathy and intranuclear rod myopathy were first described in 1999. At that time, only 15 different missense mutations were known in ACTA1. More than 60 mutations have now been identified. This review analyses this larger spectrum of mutations in ACTA1. It investigates the molecular consequences of the mutations found to date, provides a framework for genotype ‐phenotype correlation and suggests future studies in light of results of investigation of normal and mutant actin in other systems, notably the actin specific to the indirect flight muscles of Drosophila. The larger series confirms that the majority of ACTA1 mutations are dominant, a small number are recessive and most isolated cases with no previous family history have de novo dominant mutations. The severity of the disease caused ranges from lack of spontaneous movements at birth requiring immediate mechanical ventilation, to mild disease compatible with life to adulthood. Overall, the mutations within ACTA1 are randomly distributed throughout the protein. However, the larger series of mutations now available indicates that there may be clustering of mutations associated with some phenotypes, e.g. actin myopathy. This would suggest that interference with certain actin functions may be more associated with certain phenotypes, though the exact pathophysiology of the actin mutations remains unknown. q 2003 Elsevier B.V. All rights reserved.
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muscle disease caused by mutations in the skeletal muscle alpha actin gene acta1
Neuromuscular Disorders, 2003Co-Authors: John C Sparrow, Hayley J Durling, Carina Wallgrenpettersson, Norma B Romero, Alan H Beggs, Kristen J Nowak, Ikuya Nonaka, Nigel G LaingAbstract:Mutations in the skeletal muscle alpha-actin gene (ACTA1) associated with congenital myopathy with excess of thin myofilaments, nemaline myopathy and intranuclear rod myopathy were first described in 1999. At that time, only 15 different missense mutations were known in ACTA1. More than 60 mutations have now been identified. This review analyses this larger spectrum of mutations in ACTA1. It investigates the molecular consequences of the mutations found to date, provides a framework for genotype ‐phenotype correlation and suggests future studies in light of results of investigation of normal and mutant actin in other systems, notably the actin specific to the indirect flight muscles of Drosophila. The larger series confirms that the majority of ACTA1 mutations are dominant, a small number are recessive and most isolated cases with no previous family history have de novo dominant mutations. The severity of the disease caused ranges from lack of spontaneous movements at birth requiring immediate mechanical ventilation, to mild disease compatible with life to adulthood. Overall, the mutations within ACTA1 are randomly distributed throughout the protein. However, the larger series of mutations now available indicates that there may be clustering of mutations associated with some phenotypes, e.g. actin myopathy. This would suggest that interference with certain actin functions may be more associated with certain phenotypes, though the exact pathophysiology of the actin mutations remains unknown. q 2003 Elsevier B.V. All rights reserved.
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muscle disease caused by mutations in the skeletal muscle alpha actin gene acta1
Neuromuscular Disorders, 2003Co-Authors: John C Sparrow, Hayley J Durling, Carina Wallgrenpettersson, Norma B Romero, Alan H Beggs, Kristen J Nowak, Ikuya Nonaka, Nigel G LaingAbstract:Mutations in the skeletal muscle alpha-actin gene (ACTA1) associated with congenital myopathy with excess of thin myofilaments, nemaline myopathy and intranuclear rod myopathy were first described in 1999. At that time, only 15 different missense mutations were known in ACTA1. More than 60 mutations have now been identified. This review analyses this larger spectrum of mutations in ACTA1. It investigates the molecular consequences of the mutations found to date, provides a framework for genotype-phenotype correlation and suggests future studies in light of results of investigation of normal and mutant actin in other systems, notably the actin specific to the indirect flight muscles of Drosophila. The larger series confirms that the majority of ACTA1 mutations are dominant, a small number are recessive and most isolated cases with no previous family history have de novo dominant mutations. The severity of the disease caused ranges from lack of spontaneous movements at birth requiring immediate mechanical ventilation, to mild disease compatible with life to adulthood. Overall, the mutations within ACTA1 are randomly distributed throughout the protein. However, the larger series of mutations now available indicates that there may be clustering of mutations associated with some phenotypes, e.g. actin myopathy. This would suggest that interference with certain actin functions may be more associated with certain phenotypes, though the exact pathophysiology of the actin mutations remains unknown.
Rachel A Davey - One of the best experts on this subject based on the ideXlab platform.
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actin alpha cardiac muscle 1 gene expression is upregulated in the skeletal muscle of men undergoing androgen deprivation therapy for prostate cancer
The Journal of Steroid Biochemistry and Molecular Biology, 2017Co-Authors: Ada S Cheung, Casey De Rooy, Itamar Levinger, Kesha Rana, Michele V Clarke, Andrew Garnham, Catriona Mclean, Jeffrey D Zajac, Rachel A Davey, Mathis GrossmannAbstract:Abstract Androgen deprivation therapy (ADT) decreases muscle mass and function but no human studies have investigated the underlying genetic or cellular effects. We tested the hypothesis that ADT will lead to changes in skeletal muscle gene expression, which may explain the adverse muscle phenotype seen clinically. We conducted a prospective cohort study of 9 men with localised prostate cancer who underwent a vastus lateralis biopsy before and after 4 weeks of ADT. Next-generation RNA sequencing was performed and genes differentially expressed following ADT underwent gene ontology mining using Ingenuity Pathway Analysis. Differential expression of genes of interest was confirmed by quantitative PCR (Q-PCR) on gastrocnemius muscle of orchidectomised mice and sham controls (n = 11/group). We found that in men, circulating total testosterone decreased from 16.5 ± 4.3 nmol/L at baseline to 0.4 ± 0.15 nmol/L post-ADT (p ABCG1, ACTC1, ANKRD1, DMPK, THY1, DCLK1, CST3 were upregulated and SLC38A3 was downregulated post-ADT. Q-PCR in mouse gastrocnemius muscle confirmed that only one gene, ACTC1 was concordantly upregulated (p In conclusion, given that ACTC1 upregulation is associated with improved muscle function in certain myopathies, we hypothesise that upregulation of ACTC1 may represent a compensatory response to ADT-induced muscle loss. Further studies will be required to evaluate the role and function of ACTC1 .
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actin alpha cardiac muscle 1 gene expression is upregulated in the skeletal muscle of men undergoing androgen deprivation therapy for prostate cancer
The Journal of Steroid Biochemistry and Molecular Biology, 2017Co-Authors: Ada S Cheung, Casey De Rooy, Itamar Levinger, Kesha Rana, Michele V Clarke, Andrew Garnham, Catriona Mclean, Jeffrey D Zajac, Jackie M Y How, Rachel A DaveyAbstract:Androgen deprivation therapy (ADT) decreases muscle mass and function but no human studies have investigated the underlying genetic or cellular effects. We tested the hypothesis that ADT will lead to changes in skeletal muscle gene expression, which may explain the adverse muscle phenotype seen clinically. We conducted a prospective cohort study of 9 men with localised prostate cancer who underwent a vastus lateralis biopsy before and after 4 weeks of ADT. Next-generation RNA sequencing was performed and genes differentially expressed following ADT underwent gene ontology mining using Ingenuity Pathway Analysis. Differential expression of genes of interest was confirmed by quantitative PCR (Q-PCR) on gastrocnemius muscle of orchidectomised mice and sham controls (n=11/group). We found that in men, circulating total testosterone decreased from 16.5±4.3nmol/L at baseline to 0.4±0.15nmol/L post-ADT (p<0.001). RNA sequencing identified 19 differentially expressed genes post-ADT (all p<0.05 after adjusting for multiple testing). Gene ontology mining identified 8 genes to be of particular interest due to known roles in androgen-mediated signalling; ABCG1, ACTC1, ANKRD1, DMPK, THY1, DCLK1, CST3 were upregulated and SLC38A3 was downregulated post-ADT. Q-PCR in mouse gastrocnemius muscle confirmed that only one gene, ACTC1 was concordantly upregulated (p<0.01) in orchidectomised mice compared with controls. In conclusion, given that ACTC1 upregulation is associated with improved muscle function in certain myopathies, we hypothesise that upregulation of ACTC1 may represent a compensatory response to ADT-induced muscle loss. Further studies will be required to evaluate the role and function of ACTC1.
