Functional assessment of Paget's disease-causing mutations in sequestosome-1 (Q8STM1)

2013 ◽  
Author(s):  
Eman Azzam ◽  
Miep Helfrich ◽  
Lynne Hocking
Keyword(s):  
Functional Assessment ◽  
Paget’S Disease ◽  
Paget's Disease ◽  
Sequestosome 1

scholarly journals p62/sequestosome 1 deficiency accelerates osteoclastogenesisin vitroand leads to Paget's disease–like bone phenotypes in mice

2018 ◽  
Vol 293 (24) ◽  
pp. 9530-9541 ◽  
Author(s):  
Frank Zach ◽  
Franziska Polzer ◽  
Alexandra Mueller ◽  
André Gessner
Keyword(s):  
Paget’S Disease ◽  
Paget's Disease ◽  
Sequestosome 1

scholarly journals Pattern of SQSTM1 Gene Variants in a Hungarian Cohort of Paget’s Disease of Bone

2020 ◽  
Author(s):  
Judit Donáth ◽  
Bernadett Balla ◽  
Márton Pálinkás ◽  
Rita Rásonyi ◽  
Gyula Vastag ◽  
...  
Keyword(s):  
Mutation Screening ◽  
Paget’S Disease ◽  
Paget's Disease ◽  
Paget’S Disease Of Bone ◽  
Gene Variants ◽  
Eastern European ◽  
Paget's Disease Of Bone ◽  
Genetic Studies ◽  
Mutation Status ◽  
Sequestosome 1

Abstract Paget’s disease of bone (PDB) is characterized by focal or multifocal increase in bone turnover. One of the most well-established candidate genes for susceptibility to PDB is Sequestosome 1 (SQSTM1). Mutations in SQSTM1 have been documented among Western-European, British and American patients with PDB. However, there is no information on SQSTM1 mutation status in PDB patients from the Central- and Eastern-European regions. In this study, we conducted a mutation screening for SQSTM1 gene variants in 82 PDB patients and 100 control participants in Hungary. Mutations of SQSTM1 were detected in 18 PDB patients (21.95%); associations between genotype and clinical characteristics were also analyzed. Altogether, six different exonic alterations, including two types of UTR variants in the SQSTM1 gene, were observed in our PDB patients. Similarly, to previous genetic studies on Paget’s disease, our most commonly detected variant was the c.1175C > T (p.Pro392Leu) in nine cases (four in monostotic and five in polyostotic form). We have surveyed the germline SQSTM1 variant distribution among Hungarian patients with PDB. We also highlighted that the pattern of the analyzed disease-associated pathophysiological parameters could partially discriminate PDB patients with normal or mutant SQSTM1 genotype. However, our findings also underline and strengthen that not solely SQSTM1 stands in the background of the complex PDB etiology.

scholarly journals Molecular insights into an ancient form of Paget’s disease of bone

2019 ◽  
Vol 116 (21) ◽  
pp. 10463-10472 ◽  
Author(s):  
Barry Shaw ◽  
Carla L. Burrell ◽  
Darrell Green ◽  
Ana Navarro-Martinez ◽  
Daniel Scott ◽  
...  
Keyword(s):  
Direct Sequencing ◽  
Paget’S Disease ◽  
Paget's Disease ◽  
Paget’S Disease Of Bone ◽  
Paget's Disease Of Bone ◽  
North West ◽  
Sequestosome 1 ◽  
The North ◽  
History Of ◽  
Skeletal Samples

Paget’s disease of bone (PDB) is a chronic skeletal disorder that can affect one or several bones in individuals older than 55 y of age. PDB-like changes have been reported in archaeological remains as old as Roman, although accurate diagnosis and natural history of the disease is lacking. Six skeletons from a collection of 130 excavated at Norton Priory in the North West of England, which dates to medieval times, show atypical and extensive pathological changes resembling contemporary PDB affecting as many as 75% of individual skeletons. Disease prevalence in the remaining collection is high, at least 16% of adults, with age at death estimations as low as 35 y. Despite these atypical features, paleoproteomic analysis identified sequestosome 1 (SQSTM1) or p62, a protein central to the pathological milieu of PDB, as one of the few noncollagenous human sequences preserved in skeletal samples. Targeted proteomic analysis detected >60% of the ancient p62 primary sequence, with Western blotting indicating p62 abnormalities, including in dentition. Direct sequencing of ancient DNA excluded contemporary PDB-associated SQSTM1 mutations. Our observations indicate that the ancient p62 protein is likely modified within its C-terminal ubiquitin-associated domain. Ancient miRNAs were remarkably preserved in an osteosarcoma from a skeleton with extensive disease, with miR-16 expression consistent with that reported in contemporary PDB-associated bone tumors. Our work displays the use of proteomics to inform diagnosis of ancient diseases such as atypical PDB, which has unusual features presumably potentiated by yet-unidentified environmental or genetic factors.

Sequestosome 1 (SQSTM1) Mutations in Paget’s Disease of Bone from the United States

2008 ◽  
Vol 82 (4) ◽  
pp. 271-277 ◽  
Author(s):  
Emily C. Rhodes ◽  
Teresa L. Johnson-Pais ◽  
Frederick R. Singer ◽  
Donna P. Ankerst ◽  
Jan M. Bruder ◽  
...  
Keyword(s):  
United States ◽  
Paget’S Disease ◽  
The United States ◽  
Paget's Disease ◽  
Paget’S Disease Of Bone ◽  
Paget's Disease Of Bone ◽  
Sequestosome 1

Genetics of Paget's disease of bone

2005 ◽  
Vol 109 (3) ◽  
pp. 257-263 ◽  
Author(s):  
Anna Daroszewska ◽  
Stuart H. Ralston
Keyword(s):  
Paget’S Disease ◽  
Nuclear Factor Κb ◽  
Paget's Disease ◽  
Paget’S Disease Of Bone ◽  
Signalling Pathway ◽  
Common Disease ◽  
Paget's Disease Of Bone ◽  
Gene Encoding ◽  
Sequestosome 1 ◽  
Candidate Loci

PDB (Paget's disease of bone) is a common condition characterized by focal increases in bone turnover affecting one or more sites throughout the skeleton. Genetic factors are important in the pathogenesis of PDB and many families have been described where PDB is inherited in an autosomal-dominant fashion. Several candidate loci for susceptibility to PDB and related syndromes have been identified by genome-wide scans and recent evidence suggests that mutations in genes that encode components of the RANK [receptor activator of NF-κB (nuclear factor-κB)]/NF-κB signalling pathway play an important role in the pathogenesis of this group of diseases. Insertion mutations in the TNFRSF11A gene encoding RANK have been identified as the cause of familial expansile osteolysis, some cases of early onset PDB and expansile skeletal hyperphosphatasia. Inactivating mutations in the TNFRSF11B gene that encodes OPG (osteoprotegerin) have been found to cause the syndrome of juvenile PDB. Polymorphisms in OPG also appear to increase the risk of developing PDB. The most important causal gene for classical PDB is Sequestosome 1 (SQSTM1), which is a scaffold protein in the NF-κB signalling pathway, and mutations affecting the UBA (ubiquitin-associated) domain of this protein occur in between 20–50% of familial and 10–20% of sporadic PDB cases. The rare syndrome of IBMPFD (inclusion body myopathy, PDB and fronto-temporal dementia) is due to mutations in the VCP gene and these also cluster in the domain of VCP that interacts with ubiquitin, suggesting a common disease mechanism with SQSTM1-mediated PDB.

scholarly journals Characterization of a Non-UBA Domain Missense Mutation of Sequestosome 1 (SQSTM1) in Paget's Disease of Bone

2009 ◽  
Vol 24 (4) ◽  
pp. 632-642 ◽  
Author(s):  
Dereen Najat ◽  
Thomas Garner ◽  
Thilo Hagen ◽  
Barry Shaw ◽  
Paul W Sheppard ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Paget’S Disease ◽  
Paget's Disease ◽  
Paget’S Disease Of Bone ◽  
Paget's Disease Of Bone ◽  
Sequestosome 1 ◽  
Uba Domain

Structural and functional studies of mutations affecting the UBA domain of SQSTM1 (p62) which cause Paget's disease of bone

2004 ◽  
Vol 32 (5) ◽  
pp. 728-730 ◽  
Author(s):  
R. Layfield ◽  
B. Ciani ◽  
S.H. Ralston ◽  
L.J. Hocking ◽  
P.W. Sheppard ◽  
...  
Keyword(s):  
Solution Structure ◽  
Paget’S Disease ◽  
Paget's Disease ◽  
Paget’S Disease Of Bone ◽  
Missense Mutations ◽  
Paget's Disease Of Bone ◽  
Hydrophobic Patch ◽  
Sequestosome 1 ◽  
Uba Domain

Mutations affecting the UBA (ubiquitin-associated) domain of SQSTM1 (Sequestosome 1) (p62) are a common cause of Paget's disease of bone. The missense mutations resolve into those which retain [P392L (Pro392→Leu), G411S] or abolish (M404V, G425R) the ability of the isolated UBA domain to bind Lys-48-linked polyubiquitin. These effects can be rationalized with reference to the solution structure of the UBA domain, which we have determined by NMR spectroscopy. The UBA domain forms a characteristic compact three-helix bundle, with a hydrophobic patch equivalent to that previously implicated in ubiquitin binding by other UBA domains. None of the mutations affect overall folding of the UBA domain, but both M404V and G425R involve residues in the hydrophobic patch, whereas Pro-392 and Gly-411 are more remote. A simple model assuming the isolated UBA domain is functioning as a compact monomer can explain the effects of the mutations on polyubiquitin binding. The P392L and G411S mutations do however have subtle local effects on secondary structure, which may become more relevant in full-length SQSTM1. Identification of the in vivo ubiquitylated substrates of SQSTM1 will be most informative in determining the functional significance of the SQSTM1–ubiquitin interaction, and consequences of the disease-associated mutations.

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