Familial Early-Onset Paget’s Disease of Bone Associated with a Novel hnRNPA2B1 Mutation

Abstract

Paget disease of bone (PDB) is a common metabolic bone disease characterized by increased bone resorption and disorganized bone formation which affect single or multiple sites of bones. Although the exact cause of PDB is still controversial, genetic factors are considered to play an important role in PDB. Several genes involved in the differentiation or function of osteoclast were shown to be associated with PDB or related syndrome such as SQSTM1, TNFRSF11A, TNFRSF11B, and ZNF687. Multisystem proteinopathy (MSP), a newly proposed syndrome including inclusion body myopathy (IBM), PDB, frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), is mainly caused by mutation in VCP gene. In 2013, a new casual gene for MSP was identified as hnRNPA2B1 gene. This may partly account for the inherited PDB traits which is however negative for mutation in already known causative PDB genes. We investigated a Chinese family with multiple affected individuals with PDB, but none of the members showed symptoms of IBM, FTD, or ALS. Three patients were evaluated clinically, biochemically, and radiographically. To screen for the responsible mutation, whole-exome sequencing was conducted in the proband, another patient, as well as a normal individual from the family. This revealed a novel heterozygous missense mutation of hnRNPA2B1 gene (c.929C>T, p. P310L) in the two patients which was then verified in all affected individuals. We describe here a novel missense mutation in hnRNPA2B1 gene in a large pedigree affected with PDB with members who do not present other manifestations of multisystem proteinopathy, such as IBM, FTD, and ALS.

Relation between single-molecule properties and phase behavior of intrinsically disordered proteins

“…To obtain the phase coexistence envelope for an IDP sequence, we use a recently proposed CG modeling framework (28) that has already been applied to understand the sequence determinants of specific IDPs (29,30). The sequences that we consider include the low-complexity (LC) domain of FUS and four different phosphomimetic variants (7,12,29), the multivalent repetitive FUS sequences ([FUS40] n ) (28), the LC domain of hnRNPA2 and two disease-related mutants (30,32,33), the N-terminal intrinsically disordered region of LAF-1 (11) and five designed variants having similar or identical sequence composition, and the disordered C-terminal domain of TDP-43 (17). We obtain the phase coexistence using two different CG potentials for several of the sequences to check whether the results presented here are model-dependent.…”

“…An example is shown in Fig. 2B for WT hnRNPA2 (32,33); results for all other proteins are given in SI Appendix, Fig. S9.…”

Weak binding to the A2RE RNA rigidifies hnRNPA2 RRMs and reduces liquid–liquid phase separation and aggregation

“…hnRNPA2 is capable of LLPS in vitro ( 10 ), but the effect of RNA binding on hnRNPA2 LLPS is unknown. hnRNPA2 is mutated in multisystem proteinopathy (MSP), a disease with elements of ALS and FTD as well as muscle and bone degeneration ( 22 ) and Paget's disease of bone ( 23 ). These disease mutations (D290V and P298L, respectively) are located in the disordered domain C-terminal to RRMs and cause hnRNPA2 to aggregate in vitro ( 10 ), but the effect of RNA on this process is unknown.…”

Targeted sequencing of DCSTAMP in familial Paget's disease of bone

“…Given that the protein coding regions of the genome have been predicted to harbour 85% of human disease causing variants, whole exome sequencing is likely to be a more efficient way of elucidating the remaining genetic variation in human disease ( Lacey et al, 2014 ). A number of studies have utilised whole exome sequencing in the context of PDB, however these have benefited from either conducting the study in a region where the disease is exceptionally rare ( Lu et al, 2017 ; Qi et al, 2017 ), or from a large kindred ( Divisato et al, 2016 ). Targeted sequencing of genes close to or within a number of the loci identified in the GWAS has been performed, including TNFRSF11A ( Gianfrancesco et al, 2012 ), OPTN ( Obaid et al, 2015 ), RIN3 ( Vallet et al, 2015 ), and DCSTAMP ( Beauregard et al, 2014 ).…”