Heterogeneity in familial dominant Paget disease of bone and muscular dystrophy

Waggoner, Brook; Kovach, Margaret J.; Winkelman, Marc D.; Cai, Dan X.; Khardori, Romesh; Gelber, David A.; Kimonis, Virginia

doi:10.1002/ajmg.10199

Cited by 26 publications

(17 citation statements)

References 11 publications

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“…Waggoner et al reported familial myopathy with distal distribution of weakness, diaphyseal location of the bone changes, no rimmed vacuoles on muscle biopsy and no link to the VCP gene locus [12]. The family reported by Metha et al disclosed no rimmed vacuoles and no inclusion bodies in the muscle biopsy, fractures of the diaphyseal part of the bone early in life and no mutation in the VCP gene [15].…”

Section: Discussionmentioning

confidence: 99%

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Late-onset autosomal dominant limb girdle muscular dystrophy and Paget's disease of bone unlinked to the VCP gene locus

Kottlors

Moske-Eick

Huebner

et al. 2010

Journal of the Neurological Sciences

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Section: Discussionmentioning

confidence: 99%

“…However, in addition to the families with VCP gene mutations, the combination of familial Paget's disease of bone with myopathy has been previously reported in only one family unlinked to the VCP gene locus and three other unrelated families with distinct phenotypes [12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Late-onset autosomal dominant limb girdle muscular dystrophy and Paget's disease of bone unlinked to the VCP gene locus

Kottlors

Moske-Eick

Huebner

et al. 2010

Journal of the Neurological Sciences

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“…VCP mutations are not the only genetic cause of a multisystem degenerative phenotype encompassing muscle, brain and bone (Waggoner et al, 2002;Kottlors et al, 2010). For example, mutations in two paralogous RNA-binding proteins, hnRNPA1 and hnRNPA2B1 were found to cause a clinically indistinguishable syndrome but without VCP mutations (Kim et al, 2013a).…”

Section: Box 2 Clinical Syndromes Associated With Vcp Mutationsmentioning

confidence: 99%

The VCP/p97 system at a glance: connecting cellular function to disease pathogenesis

Meyer

Weihl

2014

Journal of Cell Science

363

421

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The ATPase valosin-containing protein (VCP)/p97 has emerged as a central and important element of the ubiquitin system. Together with a network of cofactors, it regulates an ever-expanding range of processes that stretch into almost every aspect of cellular physiology. Its main role in proteostasis and key functions in signaling pathways are of relevance to degenerative diseases and genomic stability. In this Cell Science at a Glance and the accompanying poster, we give a brief overview of this complex system. In addition, we discuss the pathogenic basis for VCP/p97-associated diseases and then highlight in more detail new exciting links to the translational stress response and RNA biology that further underscore the significance of the VCP/p97 system.

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“…Mutations in the valosin-containing protein (VCP) gene were the first identified cause of IBMPFD, 1,2 but reports of families without linkage to chromosome 9 established the genetic heterogeneity of the disorder. 3,4 It has recently emerged that mutations in the HNRNPA2B1 (chromosome 7) and HNRNPA1 (chromosome 12) genes account for some families with IBMPFD. 5 We first raised the possibility of a connection between IBMPFD and amyotrophic lateral sclerosis (ALS) after mutations in the VCP gene were identified in patients with familial ALS.…”

mentioning

confidence: 99%

Motor neuron involvement in multisystem proteinopathy

et al. 2013

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Objective: To explore the putative connection between inclusion body myopathy, Paget disease, frontotemporal dementia (IBMPFD) and motor neuron disease (MND).Methods: Clinical, genetic, and EMG characterization of 17 patients from 8 IBMPFD families.Results: Limb weakness was the most common clinical manifestation (present in 15 patients, median onset age 38 years, range 25-52), with unequivocal evidence of upper motor neuron dysfunction in 3. EMG, abnormal in all 17, was purely neurogenic in 4, purely myopathic in 6, and mixed neurogenic/myopathic in 7. Cognitive/behavioral impairment was detected in at least 8. Mutations in VCP (R155H, R159G, R155C) were identified in 6 families, and in hnRNPA2B1 (D290V) in another family. The genetic cause in the eighth family has not yet been identified. Conclusion:Mutations in at least 4 genes may cause IBMPFD, and its phenotypic spectrum extends beyond IBM, Paget disease, and frontotemporal dementia (FTD). Weakness, the most common and disabling manifestation, may be caused by muscle disease or MND. The acronym IBMPFD is, therefore, insufficient to describe disorders due to VCP mutations or other recently identified IBMPFD-associated genes. Instead, we favor the descriptor multisystem proteinopathy (MSP), which encompasses both the extended clinical phenotype and the previously described prominent pathologic feature of protein aggregation in affected tissues. The nomenclature MSP1, MSP2, and MSP3 may be used for VCP-, HNRNPA2B1-, and HNRNPA1-associated disease, respectively. Genetic defects in MSP implicate a range of biological mechanisms including RNA processing and protein homeostasis, both with potential relevance to the pathobiology of more common MNDs such as amyotrophic lateral sclerosis (ALS) and providing an additional link between ALS and FTD. Neurology Inclusion body myopathy (IBM) with Paget disease and frontotemporal dementia (IBMPFD) is a rare multisystem degenerative disorder named after the organ systems originally recognized to be affected-muscle, bone, and brain. Mutations in the valosin-containing protein (VCP) gene were the first identified cause of IBMPFD, 1,2 but reports of families without linkage to chromosome 9 established the genetic heterogeneity of the disorder.3,4 It has recently emerged that mutations in the HNRNPA2B1 (chromosome 7) and HNRNPA1 (chromosome 12) genes account for some families with IBMPFD. 5 We first raised the possibility of a connection between IBMPFD and amyotrophic lateral sclerosis (ALS) after mutations in the VCP gene were identified in patients with familial ALS.6 Interestingly, the original report of IBMPFD 7 almost 30 years ago described it as a "familial disorder of combined lower motor neuron degeneration and skeletal disorganization"; the presence of fasciculations, EMG evidence of chronic reinnervation, and muscle biopsy showing grouped atrophy all pointing toward a primarily neurogenic process. This family was subsequently found to have an R155Q mutation in the VCP gene. 8 Since the original description, var...

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Heterogeneity in familial dominant Paget disease of bone and muscular dystrophy

Cited by 26 publications

References 11 publications

Late-onset autosomal dominant limb girdle muscular dystrophy and Paget's disease of bone unlinked to the VCP gene locus

Late-onset autosomal dominant limb girdle muscular dystrophy and Paget's disease of bone unlinked to the VCP gene locus

The VCP/p97 system at a glance: connecting cellular function to disease pathogenesis

Motor neuron involvement in multisystem proteinopathy

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