Abstract
Transthyretin variant amyloidosis (ATTRv) is a rare autosomal dominant disease characterized by the accumulation of amyloid in many organs, mostly causing a sensory-motor neuropathy, cardiomyopathy, and dysautonomia. The aim of the study was to report microRNAs (miRNAs) expression profile identified in the blood of ATTRv patients. Ten ATTRv patients, 10 asymptomatic carriers of transthyretin variant (TTRv), 10 patients with Charcot-Marie-Tooth (CMT) disease, and 10 healthy controls were studied. Human Schwann cells cultures were used to study the regulatory effects of miR-150-5p on the expression of cAMP response element-binding protein (CREB), brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF). ATTRv patients had 33 miRNAs up-regulated and 48 down-regulated versus healthy controls; 9 miRNAs were up-regulated and 30 down-regulated versus CMT patients; 19 miRNAs were up-regulated and 38 down-regulated versus asymptomatic TTRv carriers. Twelve out of the 19 upregulated miRNAs had a fold increase higher than 100. The validation experiment indicated miR-150-5p as a valuable biomarker to differentiate ATTRv patients from asymptomatic TTRv carriers (AUC: 0.9728; p < 0.0001). Schwann cells culture model demonstrated that miR-150-5p is a powerful negative regulator of CREB, BDNF, and NGF genes. Identification of deregulated miRNAs can help in understanding the complex pathomechamism underlying the development of ATTRv and related multisystemic pathology. Further investigations are needed on the role of circulating miR-150-5p to predict the shift of TTRv carriers from an asymptomatic status to symptoms appearance.
Highlights
Transthyretin (TTR) variant amyloidosis (ATTRv) is an autosomal dominant disease characterized by the formation and storage of amyloid aggregates in many organs, mostly causing an axonal sensory-motor neuropathy, cardiomyopathy, gastrointestinal dysfunction, and dysautonomia
Since several studies have reported the presence of inflammation in ATTRv nerve biopsies, some inflammatory markers have been recently investigated in serum
TNF-α, IFN-β, IL-1β, IL-8, IL-10, and IL-33 were found increased in patients versus healthy controls, but high levels of IL-33, IL-1β, and IL-10 were already seen in stage 0 asymptomatic carriers
Summary
Transthyretin (TTR) variant amyloidosis (ATTRv) is an autosomal dominant disease characterized by the formation and storage of amyloid aggregates in many organs, mostly causing an axonal sensory-motor neuropathy, cardiomyopathy, gastrointestinal dysfunction, and dysautonomia. More than 120 TTR variants (TTRv) are known with several thousand cases worldwide, and organ microRNAs Profile in ATTRv Amyloidosis involvement and clinical symptoms widely depend on the type of mutation (Adams et al, 2017). A staging system classifies patients into three stages based on severity of symptoms and the extent of disease progression, being stage 1 for symptomatic subjects with unimpaired walking, stage 2 for need of mono- or bilateral walking assistance, and stage 3 for patients relying on a wheelchair to move around. Stage 0 is an asymptomatic stage for subjects who have a TTRv but do not show yet any symptoms of the disease (Adams et al, 2016). No biomarker is available to document the progression from an asymptomatic to symptomatic status
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