VCP disease associated with Inclusion body myopathy, Paget disease of the bone and frontotemporal dementia is a progressive autosomal dominant disorder caused by mutations in Valosin containing protein gene. To establish genotype-phenotype correlations we analyzed clinical and biochemical markers from a database of 190 members in 27 families harboring ten missense mutations. Individuals were grouped into three categories: symptomatic, presymptomatic carriers and non-carriers. The symptomatic families were further divided into ten groups based on their VCP mutations. There was marked intra and inter-familial variation; and significant genotype-phenotype correlations were difficult because of small numbers. Nevertheless when comparing the two most common mutations, R155C mutation was found to be more severe, with earlier onset of myopathy and Paget (p=0.03). Survival analysis of all subjects revealed an average life span after diagnosis of myopathy and Paget of 18 and 19 years respectively, and after dementia only 6 years. R155C had a reduced survival compared to the R155H mutation (p=0.03). We identified amyotrophic lateral sclerosis (ALS) in thirteen individuals (8.9%) and Parkinson’s disease in five individuals (3%); however there was no genotypic correlation. This study represents the largest dataset of patients with VCP disease and expands our understanding of natural history and provides genotype-phenotype correlations in this unique disease.

Inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia (IBMPFD) is a progressive, fatal genetic disorder with variable penetrance, predominantly affecting three main tissue types: muscle (IBM), bone (PDB), and brain (FTD). IBMPFD is caused by mutations in the ubiquitously expressed valosin-containing protein (VCP) gene, a member of the AAA-ATPase superfamily. The majority of individuals who develop IBM have progressive proximal muscle weakness. Muscle biopsies reveal rimmed vacuoles and inclusions that are ubiquitin- and TAR DNA binding protein-43 (TDP-43)-positive using immunohistochemistry. PDB, seen in half the individuals, is caused by overactive osteoclasts and is associated clinically with pain, elevated serum alkaline phosphatase, and X-ray findings of coarse trabeculation and sclerotic lesions. FTD diagnosed at a mean age of 55 years in a third of individuals is characterized clinically by comprehension deficits, dysnomia, dyscalculia, and social unawareness. Ubiquitin- and TDP-43-positive neuronal inclusions are also found in the brain. Genotype-phenotype correlations are difficult with marked intra-familial and inter-familial variations being seen. Varied phenotypes within families include frontotemporal dementia, amyotrophic lateral sclerosis, Parkinsonism, myotonia, cataracts, and anal incompetence, among others. Cellular and animal models indicate pathogenetic disturbances in IBMPFD tissues including altered protein degradation, autophagy pathway alterations, apoptosis, and mitochondrial dysfunction. Currently, mouse and drosophila models carrying VCP mutations provide insights into the human IBMPFD pathology and are useful as tools for preclinical studies and testing of therapeutic strategies. In this review, we will explore the pathogenesis and clinical phenotype of IBMPFD caused by VCP mutations.

Dominant mutations in the valosin containing protein (VCP) gene cause inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia (IBMPFD). We have generated a knock-in mouse model with the common R155H mutation. Mice demonstrate progressive muscle weakness starting approximately at the age of 6 months. Histology of mutant muscle showed progressive vacuolization of myofibrils and centrally located nuclei, and immunostaining shows progressive cytoplasmic accumulation of TDP-43 and ubiquitin-positive inclusion bodies in quadriceps myofibrils and brain. Increased LC3-II staining of muscle sections representing increased number of autophagosomes suggested impaired autophagy. Increased apoptosis was demonstrated by elevated caspase-3 activity and increased TUNEL-positive nuclei. X-ray microtomography (uCT) images show radiolucency of distal femurs and proximal tibiae in knock-in mice and uCT morphometrics shows decreased trabecular pattern and increased cortical wall thickness. Bone histology and bone marrow derived macrophage cultures in these mice revealed increased osteoclastogenesis observed by TRAP staining suggestive of Paget bone disease. The VCPR155H/+ knock-in mice replicate the muscle, bone and brain pathology of inclusion body myopathy, thus representing a useful model for preclinical studies.

SignificanceAdvances in technology are enabling evaluation for prevention and early detection of age-related chronic diseases associated with premature mortality, such as cancer and cardiovascular diseases. These diseases kill about one-third of men and one-quarter of women between the ages of 50 and 74 years old in the United States. We used whole-genome sequencing, advanced imaging, and other clinical testing to screen 209 active, symptom-free adults. We identified a broad set of complementary age-related chronic disease risks associated with premature mortality.

T he intermediate filament (IF) protein desmin is encodedby the gene DES and contributes to the mechanical stabilization of the sarcomeres and cell contacts within the cardiac intercalated disk (ID). Desmin is the predominant IF protein of striated muscles. It belongs to the type III IF proteins characterized by a uniform assembly mechanism. In the first step of the in vitro assembly, 2 coiled-coil dimers form an antiparallel tetramer.1 These tetramers are the essential building blocks of the IF. Eight tetramers anneal in lateral orientation into unit length filaments. In the longitudinal elongation step, these unit length filaments are assembled and radially compacted into IF.2 Since the first reports on DES mutations, [3][4][5] it became obvious that DES mutations cause skeletal myopathies and different forms of cardiomyopathies. 6,7 Clinical Perspective on p 623In the meantime, >60 different DES mutations distributed over the whole sequence are known, which lead to filament formation defects with deposition of cytoplasmic desmin aggregates in the majority of cases. 8,9 However, the pathomechanisms of desmin aggregation leading to skeletal or cardiac myopathies are mechanistically not understood in detail. Moreover, 10-15 ARVC is an inherited cardiomyopathy clinically characterized by arrhythmias and predominately right ventricular dilatation leading to cardiac syncope, heart failure, or even sudden cardiac death (SCD). 16 It is well established that mutations in the genes coding for desmosomal plaque proteins cause ARVC [17][18][19] and rare forms of dilated cardiomyopathy. 20 In the cardiac muscle, desmin is found in costamers, the z-disk, and connected via plaque proteins to the cardiac desmosome within the ID. The molecular processes contributing to the destabilization of the ID through desmin filaments are fragmentarily understood. Especially, it is not known, how and which of the desmin mutations impair the connection of the IF system to the cardiac desmosome. Background-TheIn this study, we report a novel pathogenic DES mutation (c.359C>A, p.A120D), which seems to interfere particularly with the connection of desmin IF to the ID. Furthermore, we investigate whether the DES variants p.A120D and p.H326R (c.977A>G) affect the IF formation using ectopic expression cell culture systems and atomic force microscopy (AFM). These data reveal that desmin-p.A120D but not desmin-p. H326R inhibits the longitudinal assembly step, confirming its pathogenic potential. Materials and Methods Clinical Description of the PatientsIn family A, the 34-year-old female index patient (III:24) presented with atrial flutter, variable atrioventricular conduction ( Figure I in the online-only Data Supplement), and dilated atria. The average ventricular frequency was 64 bpm, and the atrial frequency was 120 bpm. In the ECG, some polymorphic premature ventricular contractions (PVCs) with a frequency of 45 to 111 bpm were detected ( Figure I in the online-only Data Supplement). The cardiological evaluation including 2-dimensional, M-m...