Alternative titles; symbols
ORPHA: 52430; DO: 0111384;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 7p15.2 | ?Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2 | 615422 | Autosomal dominant | 3 | HNRNPA2B1 | 600124 |
A number sign (#) is used with this entry because of evidence that inclusion body myopathy with Paget disease and frontotemporal dementia-2 (IBMPFD2) is caused by heterozygous mutation in the HNRNPA2B1 (600124) gene on chromosome 7p15. One such family has been reported.
For a general phenotypic description and a discussion of genetic heterogeneity of IBMPFD, see IBMPFD1 (167320).
Waggoner et al. (2002) reported a family in which autosomal dominant early-onset Paget disease of bone was associated with a scapuloperoneal type of muscular dystrophy (SPMD). Muscle histology was nonspecific. CPK levels were elevated in active forms of the disorder. PDB in this family presented primarily in the long bones and progressed to the spine and other bones.
Kim et al. (2013) studied a family (family 1, previously studied by Waggoner et al. (2002)) who manifested dominantly inherited degeneration affecting muscle, bone, brain, and motor neurons that was clinically indistinguishable from IBMPFD caused by mutation in the VCP gene (601023). The father in this pedigree had behavioral changes, weakness, muscle atrophy, and progressive skeletal abnormalities. At autopsy he was diagnosed with frontotemporal dementia, inclusion body myopathy, and Paget disease of the bone. He had 8 children, 4 of whom were affected. All had myopathy and Paget disease of the bone, with onset of slowly progressive weakness and skeletal abnormalities in their twenties. Two had cognitive impairment and 2 had motor neuron dysfunction. Muscle biopsies from one of the offspring (II5) manifesting disease in all organ systems showed atrophic fibers, central nuclei, and rimmed vacuoles characteristic of inclusion body myopathy. Whereas in normal muscle HNRNPA2B1 expression is exclusively nuclear, analysis of muscle tissue from this patient showed that the HNRNPA2B1 cleared from many nuclei and accumulated in cytoplasmic inclusions in approximately 10% of fibers. This patient also showed TDP43 (605078) pathology consisting of nuclear clearance and cytoplasmic inclusions, consistent with observations in VCP-related and sporadic inclusion body myopathy.
By molecular analyses in a family with Paget disease of bone and progressive degeneration of muscle, brain, and motor neurons, Waggoner et al. (2002) excluded all known loci for PDB, SPMD, facioscapulohumeral muscular dystrophy, ALS, Bethlem myopathy, limb-girdle muscular dystrophy, and the critical region for LGMD or hereditary inclusion body myopathy/PDB on chromosome 9p21.1-q12 (IBMPFD1; 167320). In the family described by Waggoner et al. (2002) (family 1) with inclusion body myopathy, Paget disease of the bone, and frontotemporal dementia, Kim et al. (2013) excluded mutation in the VCP gene. By exome sequencing and linkage analysis, Kim et al. (2013) identified an aspartic acid-to-valine substitution at codon 290 of HNRNPA2B1 (600124.0001) that cosegregated with disease. The evolutionarily conserved aspartic acid at this position is centered in a motif conserved in multiple human paralogs of the HNRNPA/B family.
By sequencing coding exons of the HNRNPA2B1 gene, Le Ber et al. (2014) failed to identify pathogenic mutations in a cohort of 17 unrelated French patients with sporadic or familial occurrence of multiple system proteinopathy manifest as frontotemporal lobar degeneration (FTLD) and/or amyotrophic lateral sclerosis (ALS) that segregated with Paget disease of bone (PDB), and/or inclusion body myositis (IBM). No mutations were found in 60 probands with FTLD or FTLD/ALS. By sequencing the prion-like domain of the HNRNPA2B1 gene, Seelen et al. (2014) also failed to identify any nonsynonymous mutations in 135 patients with familial ALS, 1,084 patients with sporadic ALS, 68 patients with familial FTLD, 74 patients with sporadic FTLD, and 31 patients with sporadic IBM. A splice site mutation (c.695A-G) was found in 1 patient with familial FTD, but functional studies and segregation analysis were not performed. All patients were from the Netherlands. The findings of both studies suggested that mutations in HNRNPA2B1 are a very rare cause of this spectrum of diseases.
Kim, H. J., Kim, N. C., Wang, Y.-D., Scarborough, E. A., Moore, J., Diaz, Z., MacLea, K. S., Freibaum, B., Li, S., Molliex, A., and 25 others. Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 495: 467-473, 2013. [PubMed: 23455423] [Full Text: https://doi.org/10.1038/nature11922]
Le Ber, I., Van Bortel, I., Nicolas, G., Bouya-Ahmed, K., Camuzat, A., Wallon, D., De Septenville, A., Latouche, M., Lattante, S., Kabashi, E., Jornea, L., Hannequin, D., Brice, A., the French research Network on FTLD/FTLD-ALS. hnRNPA2B1 and hnRNPA1 mutations are rare in patients with 'multisystem proteinopathy' and frontotemporal lobar degeneration phenotypes. Neurobiol. Aging 35: 934e5, 2014. Note: Electronic Article. [PubMed: 24119545] [Full Text: https://doi.org/10.1016/j.neurobiolaging.2013.09.016]
Seelen, M., Visser, A. E., Overste, D. J., Kim, H. J., Palud, A., Wong, T. H., van Swieten, J. C., Scheltens, P., Voermans, N. C., Baas, F., de Jong, J. M. B. V., van der Kooi, A. J., de Visser, M., Veldink, J. H., Taylor, J. P., Van Es, M. A., van den Berg, L. H. No mutations in hnRNPA1 and hnRNPA2B1 in Dutch patients with amyotrophic lateral sclerosis, frontotemporal dementia, and inclusion body myopathy. Neurobiol. Aging 35: 1956e9, 2014. Note: Electronic Article. [PubMed: 24612671] [Full Text: https://doi.org/10.1016/j.neurobiolaging.2014.01.152]
Waggoner, B., Kovach, M. J., Winkelman, M., Cai, D., Khardori, R., Gelber, D., Kimonis, V. E. Heterogeneity in familial dominant Paget disease of bone and muscular dystrophy. Am. J. Med. Genet. 108: 187-191, 2002. [PubMed: 11891683] [Full Text: https://doi.org/10.1002/ajmg.10199]