Clinical phenotype of adult offspring carriers of the p.Pro392Leu mutation within the SQSTM1 gene in Paget's disease of bone

Abstract

Paget's disease of bone (PDB) is a common chronic bone disorder. In the French-Canadian population, the p.Pro392Leu mutation within the SQSTM1 gene is involved in 46% of familial forms. In New Zealand, the emergence of PDB in offspring inheriting SQSTM1 mutations was reported to be delayed by a decade compared to their parents. We aimed at assessing the clinical phenotype of offspring carriers of this mutation in our French-Canadian cohort. We reviewed research records from adult offspring carriers of this mutation aged <90 years and their affected parents. In parents, we collected data on sex, age at diagnosis, number of affected bones, total serum alkaline phosphatase levels (tALPs) at diagnosis. In offspring, PDB extended phenotype assessment relying on tALPs, bone specific alkaline phosphatase levels (bALPs), procollagen type 1 amino-terminal propeptide (P1NP), whole body bone scan and skull and pelvis radiographs, was performed at inclusion from 1996 to 2009 and updated in 2016 to 2018, if not done during the past 8 years. The results showed that among the 36 offspring with an updated phenotype, four of them developed a clinical phenotype of PDB characterized by monostotic or polyostotic increased bone uptake associated with typical radiographic lesions in the affected sites, representing an incidence of 1.83 per 1000 person-years. Moreover, the age at PDB diagnosis was delayed by at least 10 years in the adult offspring carriers of the p.Pro392Leu mutation versus their affected parents. Our findings support the utility of a regular monitoring of the adult offspring without PDB but carriers of this mutation.

Bone scan findings of Paget's disease of bone in patients with VCP Multisystem Proteinopathy 1 (MSP1)

“…The mechanism of PDB pathogenesis however is similar since previous studies have shown that pathogenic variants in VCP can upregulate the NF-kB signaling pathway leading to upregulated osteoclastogenesis and bone resorption [7] and can therefore contribute to PDB [23,24,27]. Similarly, report of VCP's role in osteoblast activity involves complex regulation of bone morphogenetic protein (BMP) receptors via the VCP mediated ubiquitin/protein degradation system which may play a part in PDB pathogenesis [31,32]. Future studies should be considered to explore any pathological differences between the two entities.…”

Bone scan findings of Paget’s disease of bone in patients with VCP Multisystem Proteinopathy 1

“…Nevertheless, VCP MSP1 is a rare disease, and this series represents a significant addition to the literature. Recent studies have reported intergenerational change of PDB phenotype in general population and those with SQSTM1 mutations 20 , 36 . In our study, we did not characterize these changes as our cohort is small although we anticipate a subsequent study characterizing the severity of PDB phenotype in MSP1 patients.…”

“…The mechanism of PDB pathogenesis however is similar since previous studies have shown that pathogenic variants in VCP can upregulate the NF-kB signaling pathway leading to upregulated osteoclastogenesis and bone resorption 7 and can therefore contribute to PDB 16 – 18 . Similarly, report of VCP ’s role in osteoblast activity involves complex regulation of bone morphogenetic protein (BMP) receptors via the VCP mediated ubiquitin/protein degradation system which may play a part in PDB pathogenesis 19 , 20 . Despite the lack of treatment options for the neuromuscular and neurological manifestations of MSP1, treatment of PDB with bisphosphonates is very effective in alleviating bone pain, and preventing deformity and other comorbidities.…”

Emerging Roles of Ubiquitination in Biomolecular Condensates

“…For instance, point mutations in p62 have been discovered in both Paget’s disease of bone (PDB) and ALS [ 82 , 83 ]. Notably, 25–50% of all familial PDB patients harbor mutations in p62, predominantly located in the UBA domain [ 84 , 85 ]. Among them, M404T and G411S mutants significantly impair p62 phase separation with multi-ubiquitin chains.…”