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General Information
Name
inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 3
FlyBase ID
FBhh0000299
Overview

This report describes inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 3 (IBMPFD3), which is a subtype of inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD); IBMPFD3 exhibits autosomal dominant inheritance. The human gene implicated in this disease is HNRNPA1, which encodes heterogeneous nuclear ribonucleoprotein A1. This gene has also been associated with the disease amyotrophic lateral sclerosis 20 (ALS20, OMIM:615426, FBhh0000034). 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 ALS20 and IBMPFD in flies. An orthologous gene in human, HNRNPA2B1, is implicated in inclusion body myopathy with early-onset Paget disease without frontotemporal dementia 2 (IBMPFD2); see FBhh0000298.

Multiple UAS constructs of the human Hsap\HNRNPA1 gene have been introduced into flies, including wild-type HNRNPA1 and a gene carrying a mutational lesion implicated in IBMPFD3. Transgenic expression of mutant constructs recapitulates some of the key phenotypes of ALS20 and 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 HNRNPA1 has not been tested.

Variant(s) implicated in human disease tested (as transgenic human gene, HNRNPA1): the D262V(D314V) 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 D262V(D314V) in the human HNRNPA1 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 3
OMIM report

[INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA 3; IBMPFD3](https://omim.org/entry/615424)

Human gene(s) implicated

[HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN A1; HNRNPA1](https://omim.org/entry/164017)

Symptoms and phenotype

IBMPFD3 has been reported in a family with 5 affected sibs with a limb girdle muscular dystrophy characterized by progressive predominantly proximal muscle weakness, mildly elevated serum creatine kinase levels, myopathic findings on muscle biopsy, and Paget disease of the bone. All affected individuals showed a pattern of muscle weakness beginning in the lower proximal extremities and later spreading to the foot dorsiflexors. Muscles of the abdominal wall and iliopsoas muscle were severely affected. Scapulae were only slightly winged, and upper extremities showed no weakness except in 1 severely affected patient. Although age of onset was between 35 and 43 years, affected members recalled having been slower and clumsier than peers as children. No patient had cognitive impairment. Histology showed myopathic changes with rimmed vacuoles and inclusion bodies on muscle biopsy. There was variability regarding Paget disease of bone; of the 3 severely affected and 2 more mildly affected members, only 2 had laboratory and radiologic evidence of Paget disease. The affected mother was deceased. The pedigree strongly suggested autosomal dominant inheritance (Kottlers et al., 2010, pubmed:20116073). A subsequent study of this familyconfirmed that none of the affected members in the family had motor neuron dysfunction or cognitive impairment. Family member IV9 underwent a muscle biopsy, which showed atrophic fibers, central nuclei, and rimmed vacuoles characteristic of inclusion body myopathy (Kim et al., 2013, pubmed:23455423). [From OMIM:615424, 2016.06.06]

Genetics

IBMPFD3 is caused by heterozygous mutation in the HNRNPA1 gene. The identified mutation is an A-to-T transversion at nucleotide 941 in the long isoform of HNRNPA1 (785 in the short isoform) resulting in an asp314-to-val (D314V) (ASP262VAL, D262V in the short isoform). This mutation changed an aspartic acid conserved through Drosophila that is centered in a motif, the prion-like domain (PrLD), that is conserved in multiple human paralogs of the human HNRNPA/B family. The mutation was predicted to enhance prion-like behavior (Kim et al., 2013, pubmed:23455423). [From OMIM:164017 and OMIM:615424, 2016.06.06]

Cellular phenotype and pathology

Muscle biopsies from an affected patient showed nuclear clearance and cytoplasmic inclusions of HNRNPA1 protein in 10% of muscle fibres.

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.

HNRNPA1 encodes a member of a family of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs), which are RNA-binding proteins that associate with pre-mRNAs in the nucleus and influence pre-mRNA processing, as well as other aspects of mRNA metabolism and transport. The protein encoded by this gene is one of the most abundant core proteins of hnRNP complexes and plays a key role in the regulation of alternative splicing. Mutations in this gene have been observed in individuals with amyotrophic lateral sclerosis 20. Multiple alternatively spliced transcript variants have been found. There are numerous pseudogenes of this gene distributed throughout the genome. [provided by RefSeq, Feb 2016]

Disease synonyms
IBMPFD3
multisystem proteinopathy 3
MSP3
Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 3; IBMPFD3
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) (5 alleles)
    Models Based on Experimental Evidence ( 2 )
    Modifiers Based on Experimental Evidence ( 4 )
    Models Based on Experimental Evidence ( 1 )
    Modifiers Based on Experimental Evidence ( 0 )
    Allele
    Disease
    Interaction
    References
    Genetic Tools, Stocks and Reagents
    Sources of Stocks
    Contact lab of origin for a reagent not available from a public stock center.
    Bloomington Stock Center Disease Page
    Selected mammalian transgenes
    Allele
    Transgene
    Publicly Available Stocks
    Selected Drosophila transgenes
    Allele
    Transgene
    Publicly Available Stocks
    RNAi constructs available
    Allele
    Transgene
    Publicly Available Stocks
    Selected Drosophila classical alleles
    Allele
    Allele class
    Mutagen
    Publicly Available Stocks
    References (10)