The Experts below are selected from a list of 204 Experts worldwide ranked by ideXlab platform
Giles D J Watts - One of the best experts on this subject based on the ideXlab platform.
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vcp associated inclusion body myopathy and Paget Disease of bone knock in mouse model exhibits tissue pathology typical of human Disease
PLOS ONE, 2010Co-Authors: Mallikarjun Badadani, Giles D J Watts, Jouni Vesa, Angele Nalbandian, Masashi Kitazawa, Hailing Su, Jasmin Tanaja, Douglas C Wallace, Jogeshwar MukherjeeAbstract:Dominant mutations in the valosin containing protein (VCP) gene cause inclusion body myopathy associated with Paget's Disease of bone and frontotemporal dementia (IBMPFD). We have generated a knock-in mouse model with the common R155H mutation. Mice demonstrate progressive muscle weakness starting approximately at the age of 6 months. Histology of mutant muscle showed progressive vacuolization of myofibrils and centrally located nuclei, and immunostaining shows progressive cytoplasmic accumulation of TDP-43 and ubiquitin-positive inclusion bodies in quadriceps myofibrils and brain. Increased LC3-II staining of muscle sections representing increased number of autophagosomes suggested impaired autophagy. Increased apoptosis was demonstrated by elevated caspase-3 activity and increased TUNEL-positive nuclei. X-ray microtomography (uCT) images show radiolucency of distal femurs and proximal tibiae in knock-in mice and uCT morphometrics shows decreased trabecular pattern and increased cortical wall thickness. Bone histology and bone marrow derived macrophage cultures in these mice revealed increased osteoclastogenesis observed by TRAP staining suggestive of Paget bone Disease. The VCPR155H/+ knock-in mice replicate the muscle, bone and brain pathology of inclusion body myopathy, thus representing a useful model for preclinical studies.
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vcp Disease associated with myopathy Paget Disease of bone and frontotemporal dementia review of a unique disorder
Biochimica et Biophysica Acta, 2008Co-Authors: Virginia Kimonis, Giles D J Watts, Erin C Fulchiero, Jouni VesaAbstract:Abstract Inclusion body myopathy (IBM) associated with Paget Disease of the bone (PDB) and frontotemporal dementia (FTD) (now called IBMPFD), is a progressive autosomal dominant disorder that was recently identified as being caused by mutations in the VCP (p97 or CDC48) gene which plays a key role in the ubiquitin–proteasome dependent degradation of cytosolic proteins and in the retro translocation of misfolded proteins from the endoplasmic reticulum into the cytoplasm. Approximately 90% of the affected persons in the study have myopathy or muscle weakness particularly of the shoulder and hip girdles, which can lead to loss of walking ability and even death by complications of respiratory and cardiac failure. About half of affected study participants have Paget Disease of bone characterized by abnormal rates of bone growth that can result in bone pain, enlargement and fractures. Findings of premature FTD affecting behavior and personality are seen in a third of affected individuals. Within 20 IBMPFD families whose data was analyzed for this study, ten missense mutations have been identified, the majority of which are located in the N-terminal ubiquitin binding domain. Inclusions seen in the muscle, brain and heart in VCP Disease contain ubiquitin, beta amyloid and TDP-43, also seen in other neurodegenerative disorders thus implicating common pathways in their pathogenesis.
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novel vcp mutations in inclusion body myopathy associated with Paget Disease of bone and frontotemporal dementia
Clinical Genetics, 2007Co-Authors: Giles D J Watts, Sarju G Mehta, Erin C Fulchiero, Dana Thomasova, Sheena Ramdeen, David A Drachman, Conrad C Weihl, Zygmunt Jamrozik, Hubert Kwiecinski, Anna KaminskaAbstract:Inclusion body myopathy associated with Paget Disease of bone and frontotemporal dementia (IBMPFD, OMIM 167320) has recently been attributed to eight missense mutations in valosin-containing protein (VCP). We report novel VCP mutations N387H and L198W in six individuals from two families who presented with proximal muscle weakness at a mean age of diagnosis of 40 years, most losing the ability to walk within a few years of onset. Electromyographic studies in four individuals were suggestive of 'myopathic' changes, and neuropathic pattern was identified in one individual in family 1. Muscle biopsy in four individuals showed myopathic changes characterized by variable fiber size, two individuals showing rimmed vacuoles and IBM-type cytoplasmic inclusions in muscle fibers, and electron microscopy in one individual revealing abundant intranuclear inclusions. Frontotemporal dementia associated with characteristic behavioral changes including short-term memory loss, language difficulty, and antisocial behavior was observed in three individuals at a mean age of 47 years. Detailed brain pathology in one individual showed cortical degenerative changes, most severe in the temporal lobe and hippocampus. Abundant ubiquitin-positive tau-, α-synuclein-, polyglutamine repeat-negative neuronal intranuclear inclusions and only rare intracytoplasmic VCP positive inclusions were seen. These new mutations may cause structural changes in VCP and provide some insight into the functional effects of pathogenic mutations.
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inclusion body myopathy associated with Paget Disease of bone and frontotemporal dementia is caused by mutant valosin containing protein
Nature Genetics, 2004Co-Authors: Giles D J Watts, Jill Wymer, Margaret J Kovach, Sarju G Mehta, Steven Mumm, Daniel Darvish, Alan Pestronk, Michael P Whyte, Virginia KimonisAbstract:Inclusion body myopathy associated with Paget Disease of bone and frontotemporal dementia (IBMPFD) is a dominant progressive disorder that maps to chromosome 9p21.1–p12. We investigated 13 families with IBMPFD linked to chromosome 9 using a candidate-gene approach. We found six missense mutations in the gene encoding valosin-containing protein (VCP, a member of the AAA-ATPase superfamily) exclusively in all 61 affected individuals. Haplotype analysis indicated that descent from two founders in two separate North American kindreds accounted for IBMPFD in ∼50% of affected families. VCP is associated with a variety of cellular activities, including cell cycle control, membrane fusion and the ubiquitin-proteasome degradation pathway. Identification of VCP as causing IBMPFD has important implications for other inclusion-body Diseases, including myopathies, dementias and Paget Disease of bone (PDB), as it may define a new common pathological ubiquitin-based pathway.
Virginia Kimonis - One of the best experts on this subject based on the ideXlab platform.
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vcp Disease associated with myopathy Paget Disease of bone and frontotemporal dementia review of a unique disorder
Biochimica et Biophysica Acta, 2008Co-Authors: Virginia Kimonis, Giles D J Watts, Erin C Fulchiero, Jouni VesaAbstract:Abstract Inclusion body myopathy (IBM) associated with Paget Disease of the bone (PDB) and frontotemporal dementia (FTD) (now called IBMPFD), is a progressive autosomal dominant disorder that was recently identified as being caused by mutations in the VCP (p97 or CDC48) gene which plays a key role in the ubiquitin–proteasome dependent degradation of cytosolic proteins and in the retro translocation of misfolded proteins from the endoplasmic reticulum into the cytoplasm. Approximately 90% of the affected persons in the study have myopathy or muscle weakness particularly of the shoulder and hip girdles, which can lead to loss of walking ability and even death by complications of respiratory and cardiac failure. About half of affected study participants have Paget Disease of bone characterized by abnormal rates of bone growth that can result in bone pain, enlargement and fractures. Findings of premature FTD affecting behavior and personality are seen in a third of affected individuals. Within 20 IBMPFD families whose data was analyzed for this study, ten missense mutations have been identified, the majority of which are located in the N-terminal ubiquitin binding domain. Inclusions seen in the muscle, brain and heart in VCP Disease contain ubiquitin, beta amyloid and TDP-43, also seen in other neurodegenerative disorders thus implicating common pathways in their pathogenesis.
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clinical studies in familial vcp myopathy associated with Paget Disease of bone and frontotemporal dementia
American Journal of Medical Genetics Part A, 2008Co-Authors: Virginia Kimonis, Sarju G Mehta, Erin C Fulchiero, Dana Thomasova, Marzia Pasquali, Kym M Boycott, Edward G Neilan, Alex I Kartashov, Mark S Forman, Stuart TuckerAbstract:Inclusion body myopathy with Paget Disease of the bone (PDB) and/or frontotemporal dementia (IBMPFD, OMIM 167320), is a progressive autosomal dominant disorder caused by mutations in the Valousin-containing protein (VCP, p97 or CDC48) gene. IBMPFD can be difficult to diagnose. We assembled data on a large set of families to illustrate the number and type of misdiagnoses that occurred. Clinical analysis of 49 affected individuals in nine families indicated that 42 (87%) of individuals had muscle Disease. The majority were erroneously diagnosed with limb girdle muscular dystrophy (LGMD), facioscapular muscular dystrophy, peroneal muscular dystrophy, late adult onset distal myopathy, spinal muscular atrophy, scapuloperoneal muscular dystrophy, or amyotrophic lateral sclerosis (ALS) among others. Muscle biopsies showed rimmed vacuoles characteristic of an inclusion body myopathy in 7 of 18 patients (39%), however, inclusion body myopathy was correctly diagnosed among individuals in only families 5 and 15. Frontotemporal dementia (FTD) was diagnosed in 13 individuals (27%) at a mean age of 57 years (range 48.9–60.2 years); however, several individuals had been diagnosed with Alzheimer Disease. Histopathological examination of brains of three affected individuals revealed a pattern of ubiquitin positive neuronal intranuclear inclusions and dystrophic neurites. These families expand the clinical phenotype in IBMPFD, a complex disorder caused by mutations in VCP. The presence of PDB in 28 (57%) individuals suggests that measuring serum alkaline phosphatase (ALP) activity may be a useful screen for IBMPFD in patients with myopathy.
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inclusion body myopathy associated with Paget Disease of bone and frontotemporal dementia is caused by mutant valosin containing protein
Nature Genetics, 2004Co-Authors: Giles D J Watts, Jill Wymer, Margaret J Kovach, Sarju G Mehta, Steven Mumm, Daniel Darvish, Alan Pestronk, Michael P Whyte, Virginia KimonisAbstract:Inclusion body myopathy associated with Paget Disease of bone and frontotemporal dementia (IBMPFD) is a dominant progressive disorder that maps to chromosome 9p21.1–p12. We investigated 13 families with IBMPFD linked to chromosome 9 using a candidate-gene approach. We found six missense mutations in the gene encoding valosin-containing protein (VCP, a member of the AAA-ATPase superfamily) exclusively in all 61 affected individuals. Haplotype analysis indicated that descent from two founders in two separate North American kindreds accounted for IBMPFD in ∼50% of affected families. VCP is associated with a variety of cellular activities, including cell cycle control, membrane fusion and the ubiquitin-proteasome degradation pathway. Identification of VCP as causing IBMPFD has important implications for other inclusion-body Diseases, including myopathies, dementias and Paget Disease of bone (PDB), as it may define a new common pathological ubiquitin-based pathway.
Jolene J Windle - One of the best experts on this subject based on the ideXlab platform.
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mutation of the sequestosome 1 p62 gene increases osteoclastogenesis but does not induce Paget Disease
Journal of Clinical Investigation, 2007Co-Authors: Noriyoshi Kurihara, Frederick R Singer, Jolene J Windle, Yuko Hiruma, Hua Zhou, Mark A Subler, David W Dempster, Sakamuri V Reddy, Helen E Gruber, David G RoodmanAbstract:Paget Disease is the most exaggerated example of abnormal bone remodeling, with the primary cellular abnormality in the osteoclast. Mutations in the p62 (sequestosome 1) gene occur in one-third of patients with familial Paget Disease and in a minority of patients with sporadic Paget Disease, with the P392L amino acid substitution being the most commonly observed mutation. However, it is unknown how p62P392L mutation contributes to the development of this Disease. To determine the effects of p62P392L expression on osteoclasts in vitro and in vivo, we introduced either the p62P392L or WT p62 gene into normal osteoclast precursors and targeted p62P392L expression to the osteoclast lineage in transgenic mice. p62P392L-transduced osteoclast precursors were hyperresponsive to receptor activator of NF-κB ligand (RANKL) and TNF-α and showed increased NF-κB signaling but did not demonstrate increased 1,25-(OH)2D3 responsivity, TAFII-17 expression, or nuclear number per osteoclast. Mice expressing p62P392L developed increased osteoclast numbers and progressive bone loss, but osteoblast numbers were not coordinately increased, as is seen in Paget Disease. These results indicate that p62P392L expression on osteoclasts is not sufficient to induce the full Pagetic phenotype but suggest that p62 mutations cause a predisposition to the development of Paget Disease by increasing the sensitivity of osteoclast precursors to osteoclastogenic cytokines.
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Paget Disease of bone
Journal of Clinical Investigation, 2005Co-Authors: David G Roodman, Jolene J WindleAbstract:Paget Disease of bone (PD) is characterized by excessive bone resorption in focal areas followed by abundant new bone formation, with eventual replacement of the normal bone marrow by vascular and fibrous tissue. The etiology of PD is not well understood, but one PD-linked gene and several other susceptibility loci have been identified, and paramyxoviral gene products have been detected in Pagetic osteoclasts. In this review, the pathophysiology of PD and evidence for both a genetic and a viral etiology for PD will be discussed.
Heather M. Brown - One of the best experts on this subject based on the ideXlab platform.
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Uroplakin-III to distinguish primary vulvar Paget Disease from Paget Disease secondary to urothelial carcinoma
Human Pathology, 2002Co-Authors: Heather M. Brown, Edward J. WilkinsonAbstract:Abstract Paget Disease of the vulva can be mimicked by several Disease entities histopathologically, but most of these entities can be clinically distinguished from vulvar Paget Disease. However, vulvar Paget Disease is in itself a heterogeneous group of epithelial neoplasms that can be similar both clinically and histopathologically. The subtypes of vulvar Paget Disease include primary Paget Disease arising from a pluripotent stem cell within the epithelium of the vulva, and secondary Paget Disease of the vulva. Secondary vulvar Paget Disease results from spread of an internal malignancy, most commonly from an anorectal adenocarcinoma or urothelial carcinoma of the bladder or urethra, to the vulvar epithelium. We have recently proposed that these lesions be classified as primary (of cutaneous origin) or secondary (of extracutaneous origin). These subtypes can present similarly as eczematoid skin lesions and may appear similar on routine hematoxylin and eosin–stained slides. Immunohistochemical studies can help differentiate between them. Our current study includes 17 patients with a pathologic diagnosis of vulvar Paget Disease. We performed a panel of immunohistochemical stains, including cytokeratin (CK) 7 and 20, carcinoembryonic antigen (CEA), gross cystic Disease fluid protein-15 (GCDFP-15), and uroplakin-III (UP-III). Of these 17 patients, 14 (80%) had primary intraepithelial cutaneous Paget Disease, 13 without invasion and 1 with associated invasion. Three patients had urothelial carcinoma with spread to the vulva, manifesting as secondary vulvar Paget Disease. Immunohistochemically, primary vulvar Paget Disease is immunoreactive for CK 7 and GCDFP-15, but uncommonly for CK 20. Vulvar Paget Disease secondary to anorectal carcinoma demonstrates CK 20 immunoreactivity but is usually nonreactive for CK 7 and consistently nonimmunoreactive for GCDFP-15. Vulvar Paget Disease secondary to urothelial carcinoma is immunoreactive for CK 7 and CK 20 but nonimmunoreactive for GCDFP-15. In addition, we propose the use of a new, commercially available antibody, UP-III, which is specific for urothelium and, in our experience, is immunoreactive in secondary vulvar Paget Disease of urothelial origin. The distinction between these 3 types of Paget and Paget-like lesions is essential in that the specific diagnosis has a significant influence on current treatment. The difference in surgical approach to the subtypes of vulvar Paget Disease justifies classifying them into distinct lesions, which may be aided by the use of immunohistochemistry, including UP-III. H UM P ATHOL 33:545-548. Copyright 2002, Elsevier Science (USA). All rights reserved.
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Vulvar Paget Disease of urothelial origin: A report of three cases and a proposed classification of vulvar Paget Disease *
Human Pathology, 2002Co-Authors: Edward J. Wilkinson, Heather M. BrownAbstract:Abstract Extramammary Paget Disease is generally considered a distinct entity that can involve the genital tract skin and may be associated with underlying adenocarcinoma. Evidence is presented that vulvar Paget Disease represents a heterogeneous group of epithelial neoplasms that can be similar both clinically and histopathologically. Three cases of vulvar Paget-like Disease that were manifestations of urothelial carcinoma are investigated. Vulvar Paget Disease can be classified based on the origin of the neoplastic Paget cells as either primary (of cutaneous origin) or secondary (of noncutaneous origin). Each classification has 3 subtypes: primary, intraepithelial cutaneous Paget Disease of the usual type; intraepithelial cutaneous Paget Disease with invasion, and intraepithelial cutaneous Paget Disease as a manifestation of underlying skin appendage adenocarcinoma; secondary, Paget Disease of anorectal origin, Paget Disease of urothelial origin, and Paget Disease of other origin. This subclassification is based on a review of the literature and the current study of 3 patients with Paget-like Disease of urothelial neoplastic origin. The 3 subtypes of vulvar Paget Disease studied here can present similarly as eczematoid skin or vulvar mucosal lesions and may appear similar on routine hematoxylin and eosin–stained slides. Immunohistochemical studies can be used to help differentiate them. The distinction between these 3 types of Paget-like lesions is essential in that the specific diagnosis has a significant influence on current treatment. The difference in surgical approach to the subtypes of vulvar Paget Disease justifies classifying them into distinct lesions to avoid potential confusion and unnecessary surgery. HUM PATHOL 33:549-554. Copyright 2002, Elsevier Science (USA). All rights reserved.
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vulvar Paget Disease of urothelial origin a report of three cases and a proposed classification of vulvar Paget Disease
Human Pathology, 2002Co-Authors: Edward J. Wilkinson, Heather M. BrownAbstract:Abstract Extramammary Paget Disease is generally considered a distinct entity that can involve the genital tract skin and may be associated with underlying adenocarcinoma. Evidence is presented that vulvar Paget Disease represents a heterogeneous group of epithelial neoplasms that can be similar both clinically and histopathologically. Three cases of vulvar Paget-like Disease that were manifestations of urothelial carcinoma are investigated. Vulvar Paget Disease can be classified based on the origin of the neoplastic Paget cells as either primary (of cutaneous origin) or secondary (of noncutaneous origin). Each classification has 3 subtypes: primary, intraepithelial cutaneous Paget Disease of the usual type; intraepithelial cutaneous Paget Disease with invasion, and intraepithelial cutaneous Paget Disease as a manifestation of underlying skin appendage adenocarcinoma; secondary, Paget Disease of anorectal origin, Paget Disease of urothelial origin, and Paget Disease of other origin. This subclassification is based on a review of the literature and the current study of 3 patients with Paget-like Disease of urothelial neoplastic origin. The 3 subtypes of vulvar Paget Disease studied here can present similarly as eczematoid skin or vulvar mucosal lesions and may appear similar on routine hematoxylin and eosin–stained slides. Immunohistochemical studies can be used to help differentiate them. The distinction between these 3 types of Paget-like lesions is essential in that the specific diagnosis has a significant influence on current treatment. The difference in surgical approach to the subtypes of vulvar Paget Disease justifies classifying them into distinct lesions to avoid potential confusion and unnecessary surgery. HUM PATHOL 33:549-554. Copyright 2002, Elsevier Science (USA). All rights reserved.
David G Roodman - One of the best experts on this subject based on the ideXlab platform.
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mutation of the sequestosome 1 p62 gene increases osteoclastogenesis but does not induce Paget Disease
Journal of Clinical Investigation, 2007Co-Authors: Noriyoshi Kurihara, Frederick R Singer, Jolene J Windle, Yuko Hiruma, Hua Zhou, Mark A Subler, David W Dempster, Sakamuri V Reddy, Helen E Gruber, David G RoodmanAbstract:Paget Disease is the most exaggerated example of abnormal bone remodeling, with the primary cellular abnormality in the osteoclast. Mutations in the p62 (sequestosome 1) gene occur in one-third of patients with familial Paget Disease and in a minority of patients with sporadic Paget Disease, with the P392L amino acid substitution being the most commonly observed mutation. However, it is unknown how p62P392L mutation contributes to the development of this Disease. To determine the effects of p62P392L expression on osteoclasts in vitro and in vivo, we introduced either the p62P392L or WT p62 gene into normal osteoclast precursors and targeted p62P392L expression to the osteoclast lineage in transgenic mice. p62P392L-transduced osteoclast precursors were hyperresponsive to receptor activator of NF-κB ligand (RANKL) and TNF-α and showed increased NF-κB signaling but did not demonstrate increased 1,25-(OH)2D3 responsivity, TAFII-17 expression, or nuclear number per osteoclast. Mice expressing p62P392L developed increased osteoclast numbers and progressive bone loss, but osteoblast numbers were not coordinately increased, as is seen in Paget Disease. These results indicate that p62P392L expression on osteoclasts is not sufficient to induce the full Pagetic phenotype but suggest that p62 mutations cause a predisposition to the development of Paget Disease by increasing the sensitivity of osteoclast precursors to osteoclastogenic cytokines.
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Paget Disease of bone
Journal of Clinical Investigation, 2005Co-Authors: David G Roodman, Jolene J WindleAbstract:Paget Disease of bone (PD) is characterized by excessive bone resorption in focal areas followed by abundant new bone formation, with eventual replacement of the normal bone marrow by vascular and fibrous tissue. The etiology of PD is not well understood, but one PD-linked gene and several other susceptibility loci have been identified, and paramyxoviral gene products have been detected in Pagetic osteoclasts. In this review, the pathophysiology of PD and evidence for both a genetic and a viral etiology for PD will be discussed.
