Multisystem proteinopathy due to a homozygous p.Arg159His VCP mutation

Abstract

ObjectiveTo assess the clinical, radiologic, myopathologic, and proteomic findings in a patient manifesting a multisystem proteinopathy due to a homozygous valosin-containing protein gene (VCP) mutation previously reported to be pathogenic in the heterozygous state.MethodsWe studied a 36-year-old male index patient and his father, both presenting with progressive limb-girdle weakness. Muscle involvement was assessed by MRI and muscle biopsies. We performed whole-exome sequencing and Sanger sequencing for segregation analysis of the identified p.Arg159His VCP mutation. To dissect biological disease signatures, we applied state-of-the-art quantitative proteomics on muscle tissue of the index case, his father, 3 additional patients with VCP-related myopathy, and 3 control individuals.ResultsThe index patient, homozygous for the known p.Arg159His mutation in VCP, manifested a typical VCP-related myopathy phenotype, although with a markedly high creatine kinase value and a relatively early disease onset, and Paget disease of bone. The father exhibited a myopathy phenotype and discrete parkinsonism, and multiple deceased family members on the maternal side of the pedigree displayed a dementia, parkinsonism, or myopathy phenotype. Bioinformatic analysis of quantitative proteomic data revealed the degenerative nature of the disease, with evidence suggesting selective failure of muscle regeneration and stress granule dyshomeostasis.ConclusionWe report a patient showing a multisystem proteinopathy due to a homozygous VCP mutation. The patient manifests a severe phenotype, yet fundamental disease characteristics are preserved. Proteomic findings provide further insights into VCP-related pathomechanisms.

Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness

“…Both sets of parents were heterozygous for the respective variants. The mother of the homozygous VCP patient remained asymptomatic at the time of examination, while the father presented with proximal weakness and atrophy of the upper and lower limbs, and rimmed vacuoles on histopathology, 16 as would be expected for this previously reported dominant variant. 17 On the other hand, the parents of the homozygous FLNC patient were both clinically unaffected on examination.…”

Inhibition of VCP preserves retinal structure and function in autosomal dominant retinal degeneration

“…The ATP hydrolyzing activity of VCP is indispensable for its function, and ATP consumption is required to extract incorrectly folded proteins from the membranes of the ER or mitochondria (25). (21,(26)(27)(28)(29)(30). In these conditions, the dysfunction of VCP is considered to result in the deregulation of the proteostasis network (26,31).…”

“…VCP mutations have been associated with several diseases. Point mutations have been linked to multisystem proteinopathy (MSP), also known as IBMPFD (Inclusion Body Myopathy associated with Paget’s disease of the bone and Frontotemporal Dementia) and amyotrophic lateral sclerosis (ALS) (21, 26–30). In these conditions, the dysfunction of VCP is considered to result in the deregulation of the proteostasis network (26, 31).…”

Multisystem proteinopathy: Where myopathy and motor neuron disease converge

“…Neurogenic features, such as angular atrophic fibers, may also be seen (Figure 3B). 17 MHC‐1 staining shows variable degrees of sarcolemmal and sarcoplasmic staining.…”

“…The myopathy in MSP is characterized by slowly progressive weakness and atrophy of skeletal muscles. There is typically proximal and distal weakness of upper and lower extremity muscles, foot drop, and scapular winging (Figure 1) 12 ; paraspinal muscles are occasionally involved 17 . Myopathologically MSP1 is characterized by cytoplasmic rimmed vacuoles containing proteins such as tau, amyloid, and TDP‐43 14 .…”