A New Gene for Susceptibility to Paget's Disease of Bone and for Multisystem Proteinopathy

Ralston, Stuart H.

doi:10.1002/jbmr.4090

Cited by 4 publications

(3 citation statements)

References 17 publications

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“…The mainstay management is supportive care, which includes physical therapy, occupational therapy, speech-language pathology, and respiratory therapy. MSP1 patients with PDB can be treated with bisphosphonates to help relieve the pain, deformity, and complications resulting from progression [ 69 ]. It is essential for these patients to receive referrals to endocrinology or rheumatology for proper PDB management.…”

Section: Discussionmentioning

confidence: 99%

Novel Variants in the VCP Gene Causing Multisystem Proteinopathy 1

Columbres

Chin

Pratti

et al. 2023

Genes

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Valosin-containing protein (VCP) gene mutations have been associated with a rare autosomal dominant, adult-onset progressive disease known as multisystem proteinopathy 1 (MSP1), or inclusion body myopathy (IBM), Paget’s disease of bone (PDB), frontotemporal dementia (FTD), (IBMPFD), and amyotrophic lateral sclerosis (ALS). We report the clinical and genetic analysis findings in five patients, three from the same family, with novel VCP gene variants: NM_007126.5 c.1106T>C (p.I369T), c.478G>A (p.A160T), and c.760A>T (p.I254F), associated with cardinal MSP1 manifestations including myopathy, PDB, and FTD. Our report adds to the spectrum of heterozygous pathogenic variants found in the VCP gene and the high degree of clinical heterogeneity. This case series prompts increased awareness and early consideration of MSP1 in the differential diagnosis of myopathies and/or PDB, dementia, or ALS to improve the diagnosis and early management of clinical symptoms.

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Section: Discussionmentioning

confidence: 99%

Novel Variants in the VCP Gene Causing Multisystem Proteinopathy 1

Columbres

Chin

Pratti

et al. 2023

Genes

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“…Indeed, all these genes predispose to a group of neurological conditions included among the MPS category, characterized by accumulation of abnormal protein aggregates within cells, either because the disease-causing mutations result in defects of protein degradation through the proteasome or because they act directly to increase the propensity of the mutated protein to form aggregates (Taylor, 2015). It remains unclear why some patients with these mutations develop PDB while others develop neurological or muscle disorders, but it is likely that the coinheritance of other variants might affect the clinical phenotype (Ralston, 2020).…”

Section: Discussionmentioning

confidence: 99%

Update on the pathogenesis and genetics of Paget’s disease of bone

Gennari

Rendina

Merlotti

et al. 2022

Front. Cell Dev. Biol.

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Studies over the past two decades have led to major advances in the pathogenesis of Paget’s disease of bone (PDB) and particularly on the role of genetic factors. Germline mutations of different genes have been identified, as a possible cause of this disorder, and most of the underlying pathways are implicated in the regulation of osteoclast differentiation and function, whereas other are involved in cell autophagy mechanisms. In particular, about 30 different germline mutations of the Sequestosome 1 gene (SQSTM1) have been described in a significant proportion of familial and sporadic PDB cases. The majority of SQSTM1 mutations affect the ubiquitin-binding domain of the protein and are associated to a more severe clinical expression of the disease. Also, germline mutations in the ZNF687 and PFN1 genes have been associated to severe, early onset, polyostotic PDB with increased susceptibly to neoplastic degeneration, particularly giant cell tumor. Mutations in the VCP (Valosin Containing Protein) gene cause the autosomal dominant syndrome “Inclusion Body Myopathy, PDB, Fronto-temporal Dementia,” characterized by pagetic manifestations, associated with myopathy, amyotrophic lateral sclerosis and fronto-temporal dementia. Moreover, germline mutations in the TNFRSF11A gene, which encodes for RANK, were associated with rare syndromes showing some histopathological, radiological, and clinical overlap with PDB and in two cases of early onset PDB-like disease. Likewise, genome wide association studies performed in unrelated PDB cases identified other potential predisposition genes and/or susceptibility loci. Thus, it is likely that polygenic factors are involved in the PDB pathogenesis in many individuals and that modifying genes may contribute in refining the clinical phenotype. Moreover, the contribution of somatic mutations of SQSTM1 gene and/or epigenetic mechanisms in the pathogenesis of skeletal pagetic abnormalities and eventually neoplastic degeneration, cannot be excluded. Indeed, clinical and experimental observations indicate that genetic susceptibility might not be a sufficient condition for the clinical development of PDB without the concomitant intervention of viral infection, in primis paramixoviruses, and/or other environmental factors (e.g., pesticides, heavy metals or tobacco exposure), at least in a subset of cases. This review summarizes the most important advances that have been made in the field of cellular and molecular biology PDB over the past decades.

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“…It is of interest that previously, mutations of PFN1 had been identified by other investigators as a cause of amyotrophic lateral sclerosis (ALS) and that when the abnormal proteins were studied in vitro , insoluble protein aggregates were formed [ 52 ]. From these observations, it would appear that PFN1- mediated PDB may represent an example of multisystem proteinopathy, recently coined as the subtype ‘multisystem proteinopathy 7 (MSP7)’ [ 53 ].…”

Section: Candidate Genes For Paget’s Diseasementioning

confidence: 99%

Genetic Determinants of Paget’s Disease of Bone

Makaram

Ralston

2021

Curr Osteoporos Rep

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Purpose of Review To provide an overview of the role of genes and loci that predispose to Paget’s disease of bone and related disorders. Recent Findings Studies over the past ten years have seen major advances in knowledge on the role of genetic factors in Paget’s disease of bone (PDB). Genome wide association studies have identified six loci that predispose to the disease whereas family based studies have identified a further eight genes that cause PDB. This brings the total number of genes and loci implicated in PDB to fourteen. Emerging evidence has shown that a number of these genes also predispose to multisystem proteinopathy syndromes where PDB is accompanied by neurodegeneration and myopathy due to the accumulation of abnormal protein aggregates, emphasising the importance of defects in autophagy in the pathogenesis of PDB. Summary Genetic factors play a key role in the pathogenesis of PDB and the studies in this area have identified several genes previously not suspected to play a role in bone metabolism. Genetic testing coupled to targeted therapeutic intervention is being explored as a way of halting disease progression and improving outcome before irreversible skeletal damage has occurred.

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A New Gene for Susceptibility to Paget's Disease of Bone and for Multisystem Proteinopathy

Cited by 4 publications

References 17 publications

Novel Variants in the VCP Gene Causing Multisystem Proteinopathy 1

Novel Variants in the VCP Gene Causing Multisystem Proteinopathy 1

Update on the pathogenesis and genetics of Paget’s disease of bone

Genetic Determinants of Paget’s Disease of Bone

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