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General Information
Name
inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2
FlyBase ID
FBhh0000298
Overview

This report describes inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2 (IBMPFD2), which is a subtype of inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD); IBMPFD2 exhibits autosomal dominant inheritance. The human gene implicated in this disease is HNRNPA2B1, which encodes two proteins through alternative splicing: heterogeneous nuclear ribonucleoprotein A2 and heterogeneous nuclear ribonucleoprotein B1. There are two high-scoring fly orthologs: Hrb98DE, for which RNAi targeting constructs, alleles caused by insertional mutagenesis, and classical amorphic alleles have been generated; and Hrb87F, for which RNAi targeting constructs and classical amorphic alleles have been generated. Only Hrb98DE has been analyzed in the context of IBMPFD in flies. An orthologous gene in human, HNRNPA1, is implicated in inclusion body myopathy with early-onset Paget disease without frontotemporal dementia 3 (IBMPFD2) and amyotrophic lateral sclerosis 20 (ALS20); see FBhh0000299.

Multiple UAS constructs of the human Hsap\HNRNPA2B1 gene have been introduced into flies, including wild-type HNRNPA2B1 and a gene carrying a mutational lesion implicated in IBMPFD2. Transgenic expression of mutant constructs recapitulates some of the key phenotypes of IBMPFD, including degeneration of muscle fibers and the formation of cytoplasmic inclusions of mutant protein. Heterologous rescue of mutations in the Drosophila ortholog by expression of HNRNPA2B1 has not been tested.

Variant(s) implicated in human disease tested (as transgenic human gene, HNRNPA2B1): the D290V(D302V) variant form of the human gene has been introduced into flies. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): D302V in the fly Hrb98DE gene (corresponds to D290V(D302V) in the human HNRNPA2B1 gene).

A UAS construct of Dmel\Hrb98DE bearing a mutation that corresponds to both the mutational lesion in HNRNPA1 that is implicated in IBMPFD3 and the mutational lesion in HNRNPA2B1 that is implicated in IBMPFD2 has been introduced into flies; it recapitulates some of the key phenotypes of ALS20 and IBMPFD, including degeneration of muscle fibers and the formation of cytoplasmic inclusions of mutant protein.

[updated Jan. 2017 by FlyBase; FBrf0222196]

Disease Summary Information
Parent Disease Summary: inclusion body myopathy with Paget disease of bone and frontotemporal dementia
Symptoms and phenotype

Inclusion body myopathy associated with Paget disease of bone (PDB) and/or frontotemporal dementia (IBMPFD) is characterized by adult-onset proximal and distal muscle weakness (clinically resembling a limb-girdle muscular dystrophy syndrome), early-onset PDB, and premature frontotemporal dementia (FTD). Muscle weakness progresses to involve other limb and respiratory muscles. Cardiac failure and cardiomyopathy have been observed in later stages. PDB involves focal areas of increased bone turnover that typically lead to spine and/or hip pain and localized enlargement and deformity of the long bones; pathologic fractures occur on occasion. Early stages of FTD are characterized by dysnomia, dyscalculia, comprehension deficits, paraphasic errors, and relative preservation of memory, and later stages by inability to speak, auditory comprehension deficits for even one-step commands, alexia, and agraphia. Mean age at diagnosis for muscle disease and PDB is 42 years; for FTD, 55 years. [from GeneReviews, Inclusion Body Myopathy with Paget Disease of Bone and/or Frontotemporal Dementia, pubmed:20301649 2016.06.03]

IBMPFD is a autosomal dominant disorder linked to multiple genes, characterized by incomplete penetrance of 3 main features: disabling muscle weakness (in 90%), osteolytic bone lesions consistent with Paget disease (in 51%), and frontotemporal dementia (in 32%). Muscle weakness is an isolated symptom in about 30% of patients and the presenting symptom in greater than half of patients, suggesting that IBMPFD may commonly be seen in a neuromuscular clinic without its other syndromic features (review by Weihl et al., 2009, pubmed:19380227). [From OMIM:167320, 2016.06.03]

Specific Disease Summary: inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2
OMIM report

[INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA 2; IBMPFD2](https://omim.org/entry/615422)

Human gene(s) implicated

[HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN A2/B1; HNRNPA2B1](https://omim.org/entry/600124)

Symptoms and phenotype

IBMPFD2 has been reported in 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. Creatine phosphokinase (CPK) levels were elevated in active forms of the disorder. Paget disease of bone in this family presented primarily in the long bones and progressed to the spine and other bones (Waggoner et al., 2002, pubmed:11891683). A subsequent study of this family, patients manifested dominantly inherited degeneration affecting muscle, bone, brain, and motor neurons that was clinically indistinguishable from IBMPFD caused by mutation in the VCP gene (OMIM: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 eight children, four 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 two had motor neuron dysfunction (Kim, et al., 2013, pubmed:23455423). [From OMIM:615422, 2016.06.01]

Genetics

IBMPFD2 is caused by heterozygous mutation in the HNRNPA2B1 gene, which encodes two proteins, HNRNPA2 and HNRNPB1, through alternative splicing. [From OMIM:615422, 2016.06.01]

Cellular phenotype and pathology

Muscle biopsies from an affected patient showed nuclear clearance and cytoplasmic inclusions of HNRNPA2B1 protein in 10% of muscle fibres.

Muscle biopsies from a patient with IBMFD2 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 (OMIM:605078) pathology consisting of nuclear clearance and cytoplasmic inclusions, consistent with observations in VCP-related and sporadic inclusion body myopathy.(Kim, et al., 2013, pubmed:23455423).[From OMIM:615422, 2016.06.01]

Molecular information

Disease-associated mutations are localized to the prion-like domains (PrLD) of HNRNPA1 and HNRNPA2B1. In vitro, disease-associated mutations greatly accelerate HNRNPA1 and HNRNPA2B1 fibrillization, and directly promote nucleation of wild-type HNRNPA1 and HNRNPA2B1 into fibrils.

HNRNPA2B1 belongs to the A/B subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are RNA binding proteins and they complex with heterogeneous nuclear RNA (hnRNA). These proteins are associated with pre-mRNAs in the nucleus and appear to influence pre-mRNA processing and other aspects of mRNA metabolism and transport. While all of the hnRNPs are present in the nucleus, some seem to shuttle between the nucleus and the cytoplasm. The hnRNP proteins have distinct nucleic acid binding properties. The protein encoded by this gene has two repeats of quasi-RRM domains that bind to RNAs. This gene has been described to generate two alternatively spliced transcript variants which encode different isoforms. [provided by RefSeq, Jul 2008]

The HNRNPA2B1 gene encodes two major proteins, HNRNPA2 and HNRNPB1, through alternative splicing. HNRNPA/B proteins, such as HNRNPA2 and HNRNPB1, are involved in packaging nascent mRNA, in alternative splicing, and in cytoplasmic RNA trafficking, translation, and stabilization. HNRNPA2 and HNRNPB1 also appear to function in telomere maintenance, cell proliferation and differentiation, and glucose transport (Moran-Jones et al., 2005, pubmed:15659580; Iwanaga et al., 2005, pubmed:15964549). [From OMIM:600124, 2016.06.01]

Disease synonyms
IBMPFD2
multisystem proteinopathy 2
MSP2
Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2; IBMPFD2
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

Many to many: 5 human to 4 Drosophila.

Other mammalian ortholog(s) used
    D. melanogaster Gene Information (1)
    Gene Snapshot
    Heterogeneous nuclear ribonucleoprotein at 98DE (Hrb98DE) encodes a nuclear RNA-binding protein. It controls hnRNA stability, splicing, IRES-dependent translation, and translational repression. It represents one of the main targets of the poly(ADP-ribosyl)ation pathway. It also regulates tissue polarity patterning and germ-line stem cell fate. [Date last reviewed: 2019-03-07]
    Gene Groups / Pathways
    Comments on ortholog(s)

    Ortholog of human HNRNPA2B1, HNRNPA3, HNRNPA1, HNRNPA1L2, and HNRNPA0 (4 Drosophila to 5 human; additional more distantly related gene(s) in both species). Dmel\Hrb98DE shares 50% identity and 64% similarity with human HNRNPA2B1, 50% identity and 62% similarity with human HNRNPA3, 49% identity and 63% similarity with human HNRNPA1L2, 48% identity and 64% similarity with human HNRNPA1, and 44% identity and 59% similarity with human HNRNPA0.

    Orthologs and Alignments from DRSC
    DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
    Synthetic Gene(s) Used (0)
    Summary of Physical Interactions (27 groups)
    protein-protein
    Interacting group
    Assay
    References
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    experimental knowledge based
    pull down, autoradiography
    experimental knowledge based
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    proximity-dependent biotin identification, Identification by mass spectrometry
    anti tag coimmunoprecipitation, anti tag western blot
    anti tag coimmunoprecipitation, western blot
    experimental knowledge based
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti bait coimmunoprecipitation, molecular weight estimation by autoradiography, molecular weight estimation by staining
    anti tag coimmunoprecipitation, western blot
    far western blotting, Identification by mass spectrometry
    RNA-protein
    Interacting group
    Assay
    References
    anti bait coimmunoprecipitation, nucleotide sequence identification
    anti bait coimmunoprecipitation, reverse transcription pcr
    anti tag coimmunoprecipitation, quantitative reverse transcription pcr
    anti tag coimmunoprecipitation, nucleic acid uv cross-linking assay, tag visualisation, anti bait coimmunoprecipitation, reverse transcription pcr
    anti bait coimmunoprecipitation, reverse transcription pcr
    pull down, Identification by mass spectrometry
    anti bait coimmunoprecipitation, reverse transcription pcr
    anti bait coimmunoprecipitation, quantitative reverse transcription pcr, electrophoretic mobility shift assay, tag visualisation, nucleic acid uv cross-linking assay, reverse transcription pcr
    anti bait coimmunoprecipitation, reverse transcription pcr
    RNA-RNA
    Interacting group
    Assay
    References
    luminiscence technology
    Alleles Reported to Model Human Disease (Disease Ontology) (7 alleles)
    Models Based on Experimental Evidence ( 2 )
    Modifiers Based on Experimental Evidence ( 4 )
    Models Based on Experimental Evidence ( 2 )
    Modifiers Based on Experimental Evidence ( 3 )
    Genetic Tools, Stocks and Reagents
    References (10)