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Frontiers in Genetics 2020Hereditary sensory and autonomic neuropathies (HSANs) are a rare and severe group of sensory axonal neuropathies. HSANs have been classified into eight groups based on...
Hereditary sensory and autonomic neuropathies (HSANs) are a rare and severe group of sensory axonal neuropathies. HSANs have been classified into eight groups based on mode of inheritance, clinical features, and the involved genes. HSAN-VI, perhaps the most notable type, is an autosomal recessive disease, which manifests as the severely impaired pain sensitivity, autonomic disturbances, distal myopathy, spontaneous or surgical amputations, and sometimes early death. Mutations in have been identified as the cause of HSAN-VI. encodes dystonin, a member of the plakin protein family that is involved in cytoskeletal filament networks. Dystonin has seven major isoforms in nerve, muscle, and epithelium. The present study investigated a Chinese family with HSAN and explored potential pathogenic variants using whole-exome sequencing (WES). Variants were screened and filtered through bioinformatics analysis and prediction of variant pathogenicity. Co-segregation analysis was subsequently conducted. We identified compound heterozygous variants of (c.3304G>A, p.V1102I and c.13796G>A, p.R4599H) in two patients. We reported on a Chinese family with HSAN-VI family and detected the disease-causing variants. Our description expands the spectrum of known variants and contributes to the clinical diagnosis of HSAN-VI.
PubMed: 32528525
DOI: 10.3389/fgene.2020.00492 -
Disease Models & Mechanisms May 2020Loss-of-function mutations in dystonin () can cause hereditary sensory and autonomic neuropathy type 6 (HSAN-VI) or epidermolysis bullosa simplex (EBS). Recently,...
Loss-of-function mutations in dystonin () can cause hereditary sensory and autonomic neuropathy type 6 (HSAN-VI) or epidermolysis bullosa simplex (EBS). Recently, -related diseases were recognized to be more complex than previously thought because a patient exhibited both neurological and skin manifestations, whereas others display only one or the other. A single locus produces at least three major isoforms: (neuronal isoform), (muscular isoform) and (epithelial isoform). () mice, which have mutations in , were originally identified as spontaneous mutants displaying neurological phenotypes. To reveal the mechanisms underlying the phenotypic heterogeneity of -related diseases, we investigated two mutant strains with different mutations: a spontaneous mutant ( mice) and a gene-trap mutant ( mice). The allele possesses a nonsense mutation in an exon shared by all isoforms. The allele is predicted to inactivate and isoforms but not There was a decrease in the levels of mRNA in the neural tissue of both and homozygotes. Loss of sensory and autonomic nerve ends in the skin was observed in both and mice at postnatal stages. In contrast, mRNA expression was reduced in the skin of mice but not in mice. Expression levels of Dst proteins in neural and cutaneous tissues correlated with mRNAs. Because encodes a structural protein in hemidesmosomes (HDs), we performed transmission electron microscopy. Lack of inner plaques and loss of keratin filament invasions underneath the HDs were observed in the basal keratinocytes of mice but not in those of mice; thus, the distinct phenotype of the skin of mice could be because of failure of Dst-e expression. These results indicate that distinct mutations within the locus can cause different loss-of-function patterns among isoforms, which accounts for the heterogeneous neural and skin phenotypes in mice and -related diseases.
Topics: Animals; Desmosomes; Disease Models, Animal; Dystonic Disorders; Dystonin; Gene Expression Regulation; Homozygote; Mice; Mutation; Neurons; Phenotype; Protein Isoforms; RNA, Messenger; Skin
PubMed: 32482619
DOI: 10.1242/dmm.041608 -
Disease Markers 2020Bullous pemphigoid (BP) is a common T helper 2- (Th2-) dominated autoimmune blistering skin disease with significant mortality. MicroRNAs (miRNAs), which are endogenous...
BACKGROUND
Bullous pemphigoid (BP) is a common T helper 2- (Th2-) dominated autoimmune blistering skin disease with significant mortality. MicroRNAs (miRNAs), which are endogenous noncoding RNA molecules, have been reported to be potential biomarkers for some autoimmune diseases; however, to date, there exist no reports on serum expression profiles of miRNAs in BP patients.
METHODS
A RNA quantitative PCR- (qPCR-) based array was conducted on sera from 20 active BP patients and 20 healthy controls for screening of miRNAs. Significantly dysregulated miRNAs were validated with use of qPCR as performed on sera samples of 45 active BP patients and 60 healthy controls. Serum CCL17, anti-BP180, and anti-BP230 levels were measured with use of ELISA.
RESULTS
Relative baseline expression levels of serum miR-1291 were significantly upregulated in the 45 BP patients as compared with the 60 healthy controls ( < 0.001) and significantly decreased in the disease control stage ( = 13, = 0.006). In addition, these baseline miR-1291 levels showed a significant positive correlation with the baseline levels of serum CCL17 ( < 0.001) and anti-BP180 ( = 38, = 0.024). Like that observed for miR-1291, baseline levels of serum CCL17 were also significantly elevated in the 45 BP patients compared with the 60 healthy controls ( < 0.001) and significantly decreased in the disease control stage ( = 13, = 0.002). However, for anti-BP180, baseline serum levels were significantly elevated in only 38 of the 45 BP patients and significantly decreased in the disease control stage ( = 10, = 0.004).
CONCLUSIONS
Relative expression levels of serum miR-1291 can reflect disease activity of BP. miR-1291 may function as an important new serum biomarker for BP.
Topics: Adult; Aged; Aged, 80 and over; Autoantibodies; Autoantigens; Biomarkers; Case-Control Studies; Chemokine CCL17; Dystonin; Female; Humans; Male; MicroRNAs; Middle Aged; Non-Fibrillar Collagens; Pemphigoid, Bullous; Skin; Th2 Cells; Collagen Type XVII
PubMed: 32399091
DOI: 10.1155/2020/9505312 -
Iranian Journal of Allergy, Asthma, and... Feb 2020No Abstract.
No Abstract.
Topics: Aged; Anti-Inflammatory Agents; Autoantigens; Dystonin; Female; Humans; Interleukin-10; Interleukin-18; Iran; Male; Middle Aged; Non-Fibrillar Collagens; Pemphigoid, Bullous; Collagen Type XVII
PubMed: 32245316
DOI: 10.18502/ijaai.v19i1.2423 -
Neurology. Genetics Feb 2020Hereditary sensory and autonomic neuropathy (HSAN-VI) is a recessive genetic disorder that arises because of mutations in the human dystonin gene (, previously known as...
Hereditary sensory and autonomic neuropathy (HSAN-VI) is a recessive genetic disorder that arises because of mutations in the human dystonin gene (, previously known as ). Although initial characterization of HSAN-VI reported it as a sensory neuropathy that was lethal in infancy, we now know of a number of heterozygous mutations in that result in milder forms of the disease. Akin to what we observe in the mouse model ( ), we believe that the heterogeneity of HSAN-VI can be attributed to a number of dystonin isoforms that the mutation affects. Lack of neuronal isoform dystonin-a2 is likely the universal determinant of HSAN-VI because all reported human cases are null for this isoform, as are all mouse alleles. Compensatory mechanisms by intact dystonin-a isoforms also likely play a role in regulating disease severity, although we have yet to determine what specific effect dystonin-a1 and dystonin-a3 have on the pathogenesis of HSAN-VI.
PubMed: 32042917
DOI: 10.1212/NXG.0000000000000389 -
Scientific Reports Dec 2019Aberrant expression of the Spectraplakin Dystonin (DST) has been observed in various cancers, including those of the breast. However, little is known about its role in...
Aberrant expression of the Spectraplakin Dystonin (DST) has been observed in various cancers, including those of the breast. However, little is known about its role in carcinogenesis. In this report, we demonstrate that Dystonin is a candidate tumour suppressor in breast cancer and provide an underlying molecular mechanism. We show that in MCF10A cells, Dystonin is necessary to restrain cell growth, anchorage-independent growth, self-renewal properties and resistance to doxorubicin. Strikingly, while Dystonin maintains focal adhesion integrity, promotes cell spreading and cell-substratum adhesion, it prevents Zyxin accumulation, stabilizes LATS and restricts YAP activation. Moreover, treating DST-depleted MCF10A cells with the YAP inhibitor Verteporfin prevents their growth. In vivo, the Drosophila Dystonin Short stop also restricts tissue growth by limiting Yorkie activity. As the two Dystonin isoforms BPAG1eA and BPAG1e are necessary to inhibit the acquisition of transformed features and are both downregulated in breast tumour samples and in MCF10A cells with conditional induction of the Src proto-oncogene, they could function as the predominant Dystonin tumour suppressor variants in breast epithelial cells. Thus, their loss could deem as promising prognostic biomarkers for breast cancer.
Topics: Animals; Breast Neoplasms; Cell Adhesion; Cell Line; Cell Proliferation; Cell Transformation, Neoplastic; Drosophila; Drosophila Proteins; Epithelial Cells; Female; Genes, Tumor Suppressor; HEK293 Cells; Humans; Microfilament Proteins; Nuclear Proteins; Photosensitizing Agents; Protein Isoforms; Proto-Oncogene Mas; RNA Interference; Trans-Activators; Verteporfin; YAP-Signaling Proteins
PubMed: 31882643
DOI: 10.1038/s41598-019-56296-z -
Medicine Dec 2019Pleomorphic adenoma is the most common salivary gland neoplasm with a variety of histologic appearances. Due to this diversity, precise preoperative diagnosis through... (Observational Study)
Observational Study
Pleomorphic adenoma is the most common salivary gland neoplasm with a variety of histologic appearances. Due to this diversity, precise preoperative diagnosis through fine needle aspiration cytology is difficult.This study sought to identify the differentially expressed genes in pleomorphic adenoma to aid precise diagnosis and clarify the mechanism of tumorigenesis.Suppressive subtractive hybridization was performed on pleomorphic adenoma tissues and the corresponding normal salivary gland tissues to screen of the differential expression of genes in pleomorphic adenoma.Four known genes (microfibrillar associated protein 4 [MFAP4], dystonin [DST], solute carrier family 35 [SLC35], and potassium channel tetramerization domain containing 15 [KCTD15]) were differentially expressed in the tumors compared with the genes in normal tissues. The expression profiles were further confirmed in 15 pleomorphic adenoma and corresponding normal salivary gland tissues by quantitative real-time reverse transcription-polymerase chain reaction.MFAP4, DST, SLC35, and KCTD15 gene expression could be potential biomarkers of pleomorphic adenoma for precise diagnosis.
Topics: Adenoma, Pleomorphic; Adolescent; Adult; Female; Gene Expression Profiling; Humans; Male; Middle Aged; Salivary Gland Neoplasms; Young Adult
PubMed: 31861025
DOI: 10.1097/MD.0000000000018468 -
Frontiers in Immunology 2019Bullous pemphigoid (BP) is the most prevalent autoimmune skin blistering disease and is characterized by the generation of autoantibodies against the hemidesmosomal... (Clinical Trial)
Clinical Trial
Bullous pemphigoid (BP) is the most prevalent autoimmune skin blistering disease and is characterized by the generation of autoantibodies against the hemidesmosomal proteins BP180 (type XVII collagen) and BP230. Most intriguingly, BP is distinct from other autoimmune diseases because it predominantly affects elderly individuals above the age of 75 years, raising the question why autoantibodies and the clinical lesions of BP emerges mostly in this later stage of life, even in individuals harboring known putative BP-associated germline gene variants. The mitochondrial genome (mtDNA) is a potential candidate to provide additional insights into the BP etiology; however, the mtDNA has not been extensively explored to date. Therefore, we sequenced the whole mtDNA of German BP patients ( = 180) and age- and sex-matched healthy controls ( = 188) using next generation sequencing (NGS) technology, followed by the replication study using Sanger sequencing of an additional independent BP ( = 89) and control cohort ( = 104). While the BP and control groups showed comparable mitochondrial haplogroup distributions, the haplogroup T exhibited a tendency of higher frequency in BP patients suffering from neurodegenerative diseases (ND) compared to BP patients without ND (50%; 3 in 6 BP with haplogroup T). A total of four single nucleotide polymorphisms (SNPs) in the mtDNA, namely, m.16263T>C, m.16051A>G, and m.16162A>G in the D-loop region of the mtDNA, and m.11914G>A in the mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 4 gene (), were found to be significantly associated with BP based on the meta-analysis of our NGS data and the Sanger sequencing data ( = 0.0017, = 0.0129, = 0.0076, and = 0.0132, respectively, Peto's test). More specifically, the three SNPs in the D-loop region were negatively, and the SNP in the gene was positively associated with BP. Our study is the first to interrogate the whole mtDNA in BP patients and controls and to implicate multiple novel mtDNA variants in disease susceptibility. Studies using larger cohorts and more diverse populations are warranted to explore the functional consequences of the mtDNA variants identified in this study on immune and skin cells to understand their contributions to BP pathology.
Topics: Aged; Aged, 80 and over; Autoantibodies; Autoantigens; DNA, Mitochondrial; Dystonin; Female; Genome, Mitochondrial; High-Throughput Nucleotide Sequencing; Humans; Male; NADH Dehydrogenase; Non-Fibrillar Collagens; Pemphigoid, Bullous; Polymorphism, Single Nucleotide; Collagen Type XVII
PubMed: 31824475
DOI: 10.3389/fimmu.2019.02200 -
Frontiers in Immunology 2019Bullous pemphigoid (BP) is an autoimmune blistering disease characterized by autoantibodies targeting cellular adhesion molecules. While IgE autoantibodies are... (Review)
Review
Bullous pemphigoid (BP) is an autoimmune blistering disease characterized by autoantibodies targeting cellular adhesion molecules. While IgE autoantibodies are occasionally reported in other autoimmune blistering diseases, BP is unique in that most BP patients develop an IgE autoantibody response. It is not known why BP patients develop self-reactive IgE and the precise role of IgE in BP pathogenesis is not fully understood. However, clinical evidence suggests an association between elevated IgE antibodies and eosinophilia in BP patients. Since eosinophils are multipotent effector cells, capable cytotoxicity and immune modulation, the putative interaction between IgE and eosinophils is a primary focus in current studies aimed at understanding the key components of disease pathogenesis. In this review, we provide an overview of BP pathogenesis, highlighting clinical and experimental evidence supporting central roles for IgE and eosinophils as independent mediators of disease and via their interaction. Additionally, therapeutics targeting IgE, the Th2 axis, or eosinophils are also discussed.
Topics: Antibodies, Monoclonal, Humanized; Autoantibodies; Cytokines; Dystonin; Eosinophilia; Eosinophils; Humans; Immunoglobulin E; Immunoglobulin G; Immunoglobulins, Intravenous; Pemphigoid, Bullous; Receptors, IgE
PubMed: 31636640
DOI: 10.3389/fimmu.2019.02331 -
Viruses Sep 2019The herpes simplex virus type 1 (HSV-1) UL37 gene encodes for a multifunctional component of the virion tegument, which is necessary for secondary envelopment in the...
The herpes simplex virus type 1 (HSV-1) UL37 gene encodes for a multifunctional component of the virion tegument, which is necessary for secondary envelopment in the cytoplasm of infected cells, for motility of the viral particle, and for the first steps in the initiation of virus infection. This 120 kDa protein has several known viral interacting partners, including pUL36, gK/pUL20, pUS10, and VP26, and cellular interacting proteins which include TRAF6, RIG-I, and dystonin. These interactions are likely important for the functions of pUL37 at both early and late stages of infection. We employed a genetic approach to determine essential domains and amino acid residues of pUL37 and their associated functions in cellular localization and virion morphogenesis. Using marker-rescue/marker-transfer methods, we generated a library of GFP-tagged pUL37 mutations in the HSV-1 strain KOS genome. Through viral growth and ultra-structural analysis, we discovered that the C-terminus is essential for replication. The N-terminal 480 amino acids are dispensable for replication in cell culture, although serve some non-essential function as viral titers are reduced in the presence of this truncation. Furthermore, the C-terminal 133 amino acids are important in so much that their absence leads to a lethal phenotype. We further probed the carboxy terminal half of pUL37 by alanine scanning mutagenesis of conserved residues among alphaherpesviruses. Mutant viruses were screened for the inability to form plaques-or greatly reduced plaque size-on Vero cells, of which 22 mutations were chosen for additional analysis. Viruses discovered to have the greatest reduction in viral titers on Vero cells were examined by electron microscopy (EM) and by confocal light microscopy for pUL37-EGFP cellular localization. This genetic approach identified both essential and non-essential domains and residues of the HSV-1 UL37 gene product. The mutations identified in this study are recognized as significant candidates for further analysis of the pUL37 function and may unveil previously undiscovered roles and interactions of this essential tegument gene.
Topics: Amino Acids; Animals; Cell Culture Techniques; Chlorocebus aethiops; Herpesvirus 1, Human; Mutation; Phenotype; Vero Cells; Viral Structural Proteins; Virion; Virus Assembly; Virus Replication
PubMed: 31540043
DOI: 10.3390/v11090853