Autosomal Dominant Inclusion Body Myopathy Research Articles

Abstract PO1-20-07: Valosin-containing protein (VCP)/p97: A novel breast cancer susceptibility gene?

Abstract Introduction: Mutations in the valosin-containing protein (VCP, also known as p97) gene are associated with autosomal dominant inclusion-body myopathy with early-onset Paget disease and frontotemporal dementia. VCP is an ATPase that subserves a variety of cellular functions, prominently, organelle biogenesis and ubiquitin-dependent protein degradation. Recently, VCP has also been shown to physically interact with BRCA1 and is postulated to orchestrate the response to DNA double-strand breaks, a critical molecular prelude to homologous recombination DNA repair. Moreover, VCP is also involved in the removal of trapped poly [ADP-ribose] polymerase 1 (PARP1) from chromatin and may play a key role in the response of tumor cells to PARP inhibitors. Whether VCP acts as a breast cancer predisposition gene is currently unknown. These observations raise speculation as to whether pathologic variation in VCP may predispose to breast cancer. Case Description: A 45-year-old female presented with early-age, locally advanced invasive ductal carcinoma, grade 2, ER < 1%, PR 10%, HER2 IHC 3+, FISH ratio 5.4. The patient completed 6 cycles of neoadjuvant PTH and was surgically downstaged to ypT1bN1a at the time of her left mastectomy. She declined adjuvant radiation. She received 1 dose of trastuzumab emtansine which was discontinued due to intolerance and transitioned to complete 1 year of adjuvant trastuzumab and pertuzumab. Her medical history is significant for inclusion body myopathy with Paget disease of bone and/or frontotemporal dementia, which was diagnosed at age 36 after presenting with proximal muscle weakness. Bone scan was consistent with Paget’s disease and neurocognitive testing did not identify any abnormalities. Diagnosis was confirmed via whole genome germline sequencing which identified a pathogenic variant in VCP [c.463C >G (p.Arg155Gly)]. Germline resequencing of 155 known cancer predisposition genes did not identify any pathogenic variants. Whole exome genomic analysis of the patient’s breast cancer revealed an elevated homologous recombination score ( > 42), consistent with molecularly important role of VCP in homologous recombination breast cancer DNA repair. The patient’s family history is significant for muscular dystrophy in multiple family members on her paternal side, each of whom was deceased prior to age 60. Her paternal half-sister has both inclusion body myopathy and breast cancer, and her paternal cousin was diagnosed with breast cancer at age 46 (unknown genetic testing for each). No history of cancer on her maternal side. Discussion: This case raises the intriguing question of whether the VCP gene represents a heretofore unrecognized breast cancer predisposition gene. Further investigation into the role of VCP in tumorigenesis is warranted, and additional population studies are necessary to confirm VCP’s role in breast cancer predisposition. Given that cancers with homologous recombination deficiencies benefit from PARP inhibitors and VCP is involved in the function of the PARP1 protein, patients with mutations in the VCP gene may benefit from PARP inhibition. Citation Format: Alexis LeVee, Duveen Sturgeon, Joanne Mortimer, Kevin McDonnell. Valosin-containing protein (VCP)/p97: A novel breast cancer susceptibility gene? [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-20-07.

Inclusion body myopathy with Paget disease and frontotemporal dementia (IBMPFD): clinical features including sphincter disturbance in a large pedigree

Autosomal dominant inclusion body myopathy (IBM) associated with Paget disease of bone (PDB) and frontotemporal dementia (FTD), or IBMPFD, is a rare recently described multisystem disorder caused by missense mutations...

A novel mutation in the VCP gene (G157R) in a german family with inclusion‐body myopathy with paget disease of bone and frontotemporal dementia

Mutations in the valosin-containing protein (VCP) are known to cause autosomal-dominant inclusion-body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD). We report a novel missense mutation (G157R) in the N-terminal region of the VCP gene in a German family. Family members presented with mild to moderate proximal muscle weakness, Paget disease of bone, and signs of early cognitive decline, with onset in the fourth decade. Two family members also showed signs of early hearing impairment, which was confirmed to be sensorineural in one person, a symptom not yet described in the context of IBMPFD.

No association of common VCP variants with sporadic frontotemporal dementia

Mutations in the gene for valosin containing protein (VCP) cause autosomal dominant inclusion body myopathy associated with Paget disease and frontotemporal dementia (IBMPFD). To investigate the role of this novel gene in sporadic forms of frontotemporal dementia (FTD), we genotyped 27 single nucleotide polymorphisms covering the entire VCP genomic region in 198 patients with sporadic FTD and 184 matched controls from Germany. No significant association could be demonstrated. There is no evidence, that common variants in VCP confer a strong risk to the development of sporadic FTD.

Pathological consequences of VCP mutations on human striated muscle

Mutations in the valosin-containing protein (VCP, p97) gene on chromosome 9p13-p12 cause a late-onset form of autosomal dominant inclusion body myopathy associated with Paget disease of the bone and frontotemporal dementia (IBMPFD). We report on the pathological consequences of three heterozygous VCP (R93C, R155H, R155C) mutations on human striated muscle. IBMPFD skeletal muscle pathology is characterized by degenerative changes and filamentous VCP- and ubiquitin-positive cytoplasmic and nuclear protein aggregates. Furthermore, this is the first report demonstrating that mutant VCP leads to a novel form of dilatative cardiomyopathy with inclusion bodies. In contrast to post-mitotic striated muscle cells and neurons of IBMPFD patients, evidence of protein aggregate pathology was not detected in primary IBMPFD myoblasts or in transient and stable transfected cells using wild-type-VCP and R93C-, R155H-, R155C-VCP mutants. Glutathione S-transferase pull-down experiments showed that all three VCP mutations do not affect the binding to Ufd1, Npl4 and ataxin-3. Structural analysis demonstrated that R93 and R155 are both surface-accessible residues located in the centre of cavities that may enable ligand-binding. Mutations at R93 and R155 are predicted to induce changes in the tertiary structure of the VCP protein. The search for putative ligands to the R93 and R155 cavities resulted in the identification of cyclic sugar compounds with high binding scores. The latter findings provide a novel link to VCP carbohydrate interactions in the complex pathology of IBMPFD.

Clinical and muscle magnetic resonance imaging study of an Italian family with autosomal dominant inclusion body myopathy not linked to known genetic loci

The objective was to report a clinical, pathological and muscle magnetic resonance (MR) study of an Italian family with an autosomal dominant inclusion body myopathy (AD-IBM). Eight subjects (age range 20-56 years; 5 females and 3 males) belonging to four generations were studied. Onset of disturbances (distal weakness at lower limbs) ranged from 20 to 28 years. CK levels were increased to five times. Only in an early stage oedema of involved muscles has been demonstrated by muscle MR. Quadriceps femoris was characteristically spared; in the last phases a mild involvement of the vasti became evident with persistent sparing of the rectus femori. Rimmed vacuoles and hyperphosphorylated tau filaments were evident at muscle biopsy. Linkage analysis excluded the association of the disease to chromosome loci 14q11, 17p13.1, 2p13, 19p13. The study suggests that quadriceps sparing is a characteristic feature also of AD-IBM. This finding could represent a muscle-image hallmark helpful in diagnosis of autosomal dominant muscular disorders.

Mutant valosin‐containing protein causes a novel type of frontotemporal dementia

Mutations in the valosin-containing protein (VCP) gene on chromosome 9p13-p12 recently have been shown to cause autosomal dominant inclusion body myopathy associated with Paget's disease of the bone and frontotemporal dementia. Here, we report the central nervous system autopsy findings in a 55-year-old German patient with inclusion body myopathy and frontotemporal dementia who harbors a heterozygous R155C missense mutation residing in the N-terminal CDC48 domain of VCP, which is involved in ubiquitin binding. We demonstrate that mutant VCP causes a novel type of frontotemporal dementia characterized by neuronal nuclear inclusions containing ubiquitin and VCP.

Valosin-containing protein aggregation in inclusion body myopathy associated with Paget disease of the bone and frontotemporal dementia

Mutations of the valosin containing protein (VCP) on chromosome 9p13-p12 have recently been shown to cause autosomal dominant inclusion body myopathy associated with Paget disease of the bone and frontotemporal dementia (IBMPFD). Here, we report clinical and muscle pathology findings in a 54 year old German patient harbouring a 464 G>A nucleotide substitution (R155H) in exon 5 of the VCP gene. In addition to mild fronto-temporal cognitive dysfunction and Paget disease confined to her first lumbar vertebra whole body MRI demonstrated marked signal changes in her shoulder girdle, erector spinae, hamstring and calf muscles. Analysis of a diagnostic muscle biopsy showed mild myopathic features. Indirect immunofluorescence revealed multiple fibers containing small foci of cytoplasmic VCP- and ubiquitin- positive protein aggregates. Furthermore, VCP Western blot analysis confirmed an increase of VCP protein expression in diseased muscle. Our findings indicate that VCP-related IBMPFD is a new member of the family of aggresome-associated disorders characterized by abnormal protein aggregation.

Clinical and genetic heterogeneity in chromosome 9p associated hereditary inclusion body myopathy: exclusion of GNE and three other candidate genes

We have previously reported a new autosomal dominant inclusion body myopathy clinically resembling limb girdle muscular dystrophy, associated with Paget disease of bone in the majority and frontotemporal dementia in a third of individuals. The critical locus for this unique disorder now termed IBMPFD is 9p21.1–p12, spans 5.5 Mb and contains the gene responsible for the recessive quadriceps-sparing inclusion body myopathy (IBM2). Mutation analysis of the GNE gene associated with IBM2 in affected individuals from four IBMPFD families did not identify any mutations, indicating that the two disorders are not allelic. Expression studies indicate that GNE has a tissue-specific splice pattern, with four splice variants. Mutation analysis in three other candidate genes (β-tropomyosin, NDUFB6 and SMU1) did not identify any mutations.

Clinical Delineation and Localization to Chromosome 9p13.3–p12 of a Unique Dominant Disorder in Four Families: Hereditary Inclusion Body Myopathy, Paget Disease of Bone, and Frontotemporal Dementia

Autosomal dominant myopathy, Paget disease of bone, and dementia constitute a unique disorder (MIM 605382). Here we describe the clinical, biochemical, radiological, and pathological characteristics of 49 affected (23 male, 26 female) individuals from four unrelated United States families. Among these affected individuals 90% have myopathy, 43% have Paget disease of bone, and 37% have premature frontotemporal dementia. EMG shows myopathic changes and muscle biopsy reveals nonspecific myopathic changes or blue-rimmed vacuoles. After candidate loci were excluded, a genome-wide screen in the large Illinois family showed linkage to chromosome 9 (maximum LOD score 3.64 with marker D9S301). Linkage analysis with a high density of chromosome 9 markers generated a maximum two-point LOD score of 9.29 for D9S1791, with a maximum multipoint LOD score of 12.24 between D9S304 and D9S1788. Subsequent evaluation of three additional families demonstrating similar clinical characteristics confirmed this locus, refined the critical region, and further delineated clinical features of this unique disorder. Hence, autosomal dominant inclusion body myopathy (HIBM), Paget disease of bone (PDB), and frontotemporal dementia (FTD) localizes to a 1.08–6.46 cM critical interval on 9p13.3–12 in the region of autosomal recessive IBM2.

Nitric oxide-induced oxidative stress in autosomal recessive and dominant inclusion-body myopathies.

Autosomal-recessive and autosomal-dominant hereditary inclusion-body myopathies are severe, progressive muscle diseases, characterized pathologically by vacuolated muscle fibres containing paired helical filaments. We immunostained muscle biopsy specimens from quadriceps-sparing autosomal-recessive and autosomal-dominant inclusion-body myopathy subjects, disease-control subjects and normal patients, utilizing isoform-specific antibodies against the neuronal and inducible forms of nitric oxide synthase, and antibodies against nitrotyrosine. Approximately 75% of the vacuolated muscle fibres in all recessive and dominant inclusion-body myopathy patients contained inclusions strongly immunoreactive with antibodies against neuronal and inducible nitric oxide synthase which, by immunoelectron microscopy, were colocalized to clusters of tubulofilaments (previously shown, by us, to be paired helical filaments). Strong nitrotyrosine immunoreactivity was in the form of multiple dots and large granular patches, which ultrastructurally did not immunolocalize to tubulofilaments. Excess intracellular nitric oxide can combine with superoxide to produce highly toxic peroxynitrite, which can nitrate tyrosines of proteins. The presence of nitrotyrosine is indicative of nitric oxide-induced oxidative stress. Our data suggest that oxidative stress plays a role in the pathogenic cascade of hereditary inclusion-body myopathies.