Hereditary gelsolin amyloidosis (HGA) is an autosomal dominant hereditary disease characterized by corneal lattice dystrophy, peripheral neuropathy, and cutis laxa. So far, no Korean patients with HGA have been reported. A 58-yr-old man presented with involuntary facial twitching, progressive bilateral facial weakness, and tongue atrophy. His mother, maternal uncle, two sisters, and son suffered from the same symptoms. Electrophysiological studies revealed signs of chronic denervation in the cervical and lumbar regions, mild sympathetic autonomic dysfunction, and bilateral facial nerve dysfunction. Diagnostic whole-exome sequencing (WES) revealed a p.D214Y heterozygous mutation in the gelsolin gene in affected members. We present the first report of a Korean family with HGA diagnosed by WES. WES facilitated a clinical diagnosis of HGA in patients with undiagnosed neuropathies.
Amyloidosis, Familial/diagnosis/*genetics ; Asian Continental Ancestry Group/*genetics ; Base Sequence ; DNA Mutational Analysis ; Gelsolin/*genetics ; Genotype ; Heterozygote ; Humans ; Male ; Middle Aged ; Pedigree ; Polymorphism, Single Nucleotide ; Republic of Korea

OBJECTIVE: To investigate the clinical significance of SCIN gene expression and promoter methylation in patients with chronic myeloid leukemia (CML). METHODS: Real-time quantitative PCR was used to detect the expression level of SCIN in mononucleatr cells of bone marrow samples from 64 CML patients and 37 controls. The methylation levels of SCIN promoter in 65 patients with CML and 29 controls were detected by real-time quantitative methylation-specific PCR and bisulfite sequencing PCR. RESULTS: The expression level of SCIN in CML patients was significantly down-regulated (P＜0.05), compared with the control group. The down-regulation rate of SCIN expression in CML patients at chronic phase, accelerated phase and blast crisis was 61%, 67% and 75%, respectively. Spearman correlation analysis showed that the expression level of SCIN negatively correlated with the transcript level of BCR-ABL1 (R=-0.315, P＜0.05). However, there was no significant difference in clinical parameters such as sex, age, white blood cell count, hemoglobin level, platelet count, chromosome, CML staging and BCL-ABL1 transcript level between low and high SCIN expression groups of CML patients (P＞0.05). No significant difference in methylation of SCIN promoter between CML patients and controls, and no correlation between SCIN expression and promoter methylation were observed (P＞0.05). CONCLUSION The SCIN expression is down-regulated in CML patients, which may relate with the pathogenesis that is, BCR-ABL1 fusion gene induces CML tumorigenesis. The down-regulation of SCIN expression may relate with the progression of CML.
Blast Crisis ; DNA Methylation ; Down-Regulation ; Fusion Proteins, bcr-abl ; Gelsolin ; genetics ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; genetics ; Promoter Regions, Genetic

This study is aimed at gaining insights into the brain site-specific proteomic senescence signature while comparing physiologically aged brains with aging-related dementia brains (for example, Alzheimer's disease (AD)). Our study of proteomic differences within the hippocampus (Hp), parietal cortex (pCx) and cerebellum (Cb) could provide conceptual insights into the molecular mechanisms involved in aging-related neurodegeneration. Using an isobaric tag for relative and absolute quantitation (iTRAQ)-based two-dimensional liquid chromatography coupled with tandem mass spectrometry (2D-LC-MS/MS) brain site-specific proteomic strategy, we identified 950 proteins in the Hp, pCx and Cb of AD brains. Of these proteins, 31 were significantly altered. Most of the differentially regulated proteins are involved in molecular transport, nervous system development, synaptic plasticity and apoptosis. Particularly, proteins such as Gelsolin (GSN), Tenascin-R (TNR) and AHNAK could potentially act as novel biomarkers of aging-related neurodegeneration. Importantly, our Ingenuity Pathway Analysis (IPA)-based network analysis further revealed ubiquitin C (UBC) as a pivotal protein to interact with diverse AD-associated pathophysiological molecular factors and suggests the reduced ubiquitin proteasome degradation system (UPS) as one of the causative factors of AD.
Aged, 80 and over ; Alzheimer Disease/*metabolism ; Brain/*metabolism ; Female ; Gelsolin/genetics/metabolism ; Humans ; Male ; Membrane Proteins/genetics/metabolism ; Neoplasm Proteins/genetics/metabolism ; Organ Specificity ; Proteome/genetics/*metabolism ; Tenascin/genetics/metabolism ; Ubiquitin C/genetics/metabolism

Adseverin is a Ca2+-dependent actin filament-severing protein that has been reported to regulate exocytosis via rearrangements of the actin cytoskeleton in secretory cells. However, the role of adseverin in bone cells has not yet been well characterized. Here, we investigated the role of adseverin in osteoclastogenesis using primary osteoclast precursor cells. Adseverin expression was upregulated during RANKL (receptor activator of nuclear factor-kappaB ligand)-induced osteoclast differentiation. Moreover, genetic silencing of adseverin decreased the number of osteoclasts generated by RANKL. Adseverin knockdown also suppressed the RANKL-mediated induction of nuclear factor of activated T-cell c1 (NFATc1), which is a key transcription factor in osteoclastogenesis. In addition, adseverin knockdown impaired bone resorption and the secretion of bone-degrading enzymes from osteoclasts. These effects were accompanied by decreased NFATc1 expression and the activation of nuclear factor-kappaB. Collectively, our results indicate that adseverin has a crucial role in osteoclastogenesis by regulating NFATc1.
Active Transport, Cell Nucleus ; Animals ; Bone Resorption/genetics/metabolism/pathology ; Cell Differentiation ; Cells, Cultured ; Female ; Gelsolin/genetics/*metabolism ; Gene Knockdown Techniques ; Humans ; Mice, Inbred ICR ; NF-kappa B/metabolism ; NFATC Transcription Factors/*metabolism ; Osteoclasts/*cytology/metabolism/pathology ; RANK Ligand/*metabolism